The world number two already has two titles to his name in 2023 but lost the final of the Miami Open to Jannik Sinner.
Alcaraz was set to compete in Monte Carlo when the clay court season begins next week but has joined compatriot Rafael Nadal in withdrawing due to injury.
Posting on Twitter, he said: "After two months abroad, I am happy to return home but sad because I finished my last match in Miami with physical discomfort.
"After visiting my doctor in Murcia today and being evaluated, I will not be able to go to Monte Carlo to start the clay court tour.
"I have post-traumatic arthritis in my left hand and muscular discomfort in the spine that needs rest to prepare for everything that is to come."
Alcaraz's defeat to Sinner in Miami saw him cede top-spot in the ATP world rankings to Novak Djokovic, having returned to the summit in March.
The Spaniard was previously ranked number one from September 2022 until January 30, 2023.
The Russian has had a remarkable week at the Masters 1000 event that included a stunning win over 11-time champion Rafael Nadal in the quarter-finals.
Rublev continued his fine run with a 6-3 7-5 win over Casper Ruud on Saturday to ensure he will do battle against Tsitsipas in his first final at this level.
Tsitsipas comfortably saw off Dan Evans – who had beaten Novak Djokovic earlier in the tournament – winning his semi-final 6-2 6-1.
Rublev had 21 winners in his 80-minute victory over Ruud and has a record of 24-4 this season, the ATP Tour's best.
"It is an amazing feeling - it is my first [Masters] final, so I am really happy," said Rublev.
"We will see what is going to happen [in the final]. I will try to do my best.
"Casper is a really amazing player, especially on clay. Since the beginning he put a really high intensity [on the court] and was really tough.
"I knew that I needed to raise my level if I wanted to fight against him, because if I [did] not raise the level I [would] lose for sure."
Rublev defeated Tsitsipas in straight sets on his way to winning an ATP 500 title in Rotterdam last month.
Six of his eight ATP titles have come since the start of last year.
It took Tsitsipas, who has not won a tournament for 14 months, only one hour and nine minutes to see off the challenge of Evans, forcing 11 break points to the Briton's one.
"I am indeed pleased with the performance," Tsitsipas said, with the Greek yet to drop a set in Monte Carlo.
"I found ways to play at my best. It was really difficult to maintain my level of consistency and I am really happy I managed to deal with all the different moments during the match.
"I'm feeling good. I'm feeling energised. I still have plenty of gas and energy left in me. I was able to have all of my matches done in two sets, so that is a big plus.
"I am happy to be able to play that way, just take it match by match, approach each individual match with the same intensity and energy - I'm really focused for Sunday."
Rublev has won three of his six career meetings with Tsitsipas and one of their two battles on clay.
Tsitsipas will be competing in his third Masters final, having lost to Nadal and Djokovic in his two previous appearances, the last of which came two years ago in Madrid.
Overall, Tsitsipas has won just five of his 13 ATP finals.
The draw for the tournament that begins on Sunday served up the appetising prospect of a tussle between the reigning French Open champion and a player many expect to enjoy huge Roland Garros success.
Alcaraz, 18, last week became the youngest men's champion at the Miami Open, and he has soared to number 11 in the ATP rankings after sitting outside the top 100 at this time 12 months ago.
He won an ATP 250 tournament on clay last year in Umag, and an ATP 500 on the surface in Rio de Janeiro in February, but earning a Masters 1000 hard court title in Miami highlighted the scale of Alcaraz's rapid improvement.
Both he and Djokovic will receive a first-round bye in Monte Carlo, and they must then win twice to set up a meeting at the last-eight stage.
Alcaraz may have to beat the in-form Indian Wells champion Taylor Fritz in the third round, with Marin Cilic and Sebastian Korda also potential early opponents for the young Spaniard.
Djokovic will not be taking a quarter-final place for granted, either. If he navigates his opening match, the Serbian could face a dicey third-round clash with Spain's Roberto Bautista Agut or the player to whom he lost at the last-16 stage last year, Britain's Dan Evans.
Rafael Nadal is absent after suffering a stress fracture of a rib during his Indian Wells final defeat to Fritz.
World number one Djokovic, playing in his first tournament since winning a ninth Australian Open in February, suffered his first defeat of 2021 on Thursday.
Evans, who had never before reached the last eight of a Masters 1000 tournament, won 6-4 7-5 with a performance that belied his relative lack of success on clay.
The 30-year-old Briton will now meet David Goffin, who surprised fifth seed Alexander Zverev 6-4 7-6 (9-7).
"To be honest, this has been probably one of the worst matches and performances from my side I can recall in the last years," said Djokovic. "I don't want to take anything away from his win, but from my side, I just felt awful on the court overall. Just nothing worked. It's one of those days."
Saying he felt "completely the opposite" to Wednesday's win over Jannik Sinner, Djokovic added: "Just was obviously very, very windy, tough to play in these kinds of conditions against a guy like Evans who makes you move. He's very unpredictable with his shots. He dismantled my game."
Eleven-time Monte Carlo champion Nadal had no such problems in his match as he dismissed Grigor Dimitrov 6-1 6-1 in 55 minutes.
Nadal, who boasts a 14-1 career record against the Bulgarian, did not face a break point in either set against his off-colour opponent.
Dimitrov started the match with three double faults in his opening service game and was 4-0 down in each set.
"[I am] sorry for him. He played a bad match. That is the truth," said Spaniard Nadal. "He made a lot of mistakes. I was there. I was doing the right thing, but it is true that today was more his fault than my good tennis."
Nadal will face Andrey Rublev after the Russian battled past Roberto Bautista-Agut 7-6 (7-2) 5-7 6-3.
Stefanos Tsitsipas, who beat Cristian Garin 6-3 6-4, will face Alejandro Davidovich Fokina next, while Fabio Fognini's straight-sets win over Filip Krajinovic set up a meeting with Casper Ruud.
The world number two has been forced to sit out the first Masters event of the year after not meeting the vaccination requirements to enter the United States, having been deported from Australia ahead of January's Australian Open for similar reasons.
Now, a post on the 20-time grand slam champion's official website suggests he will appear on the clay surface in Monaco, where the 34-year-old resides.
Monaco currently allows those who have recovered from COVID-19 in the previous six months to enter the city-state, with Djokovic claiming to have suffered from the virus in December.
"Novak will open his 2022 clay court season in Monte-Carlo, where he won the Masters 1000 title twice, in 2013 and 2015," the post reads.
The tournament now looks set to be the second to feature Djokovic in 2022 after he lost at the quarter-finals stage of last month's Dubai Tennis Championships.
The Monte Carlo Masters begins on April 10, lasting until April 17, and Djokovic will be looking to make amends after exiting last year's tournament to Dan Evans in the last 16.
Rafael Nadal, who overtook Djokovic for the most men's singles grand slam titles with his January triumph in Australia, holds the record for the most successes in Monaco, winning the tournament on 11 occasions.
Meanwhile, with France having loosened its travel restrictions for unvaccinated people this month, Djokovic will now hope to use the Monaco outing as preparation for a first grand slam appearance of the year at Roland Garros.
The Serbian now looks increasingly likely to be permitted to defend his 2021 French Open title in May after travel restrictions had originally cast doubt on his participation.
Djokovic's status as an unvaccinated player has limited his ability to compete on the tour this year. He missed the Australian Open in January after a saga surrounding his visa eventually resulted in his deportation on public health grounds, while laws around vaccination against COVID-19 in the United States prevented him from playing at Indian Wells and Miami.
Despite his inactivity, the Serbian - whose sole appearance on tour this year came during a run to the quarter-finals in Dubai - was expected to prevail on the clay against his Spanish opponent after receiving a bye in the first round.
But there were evident signs of rust in a mistake-riddled display against the world number 46, who remarkably emerged victorious to set up a meeting with either Dan Evans or David Goffin.
The tide looked to have turned in the second set tie-break, when an exquisite whipped forehand from Djokovic sent the match to a decider.
However, Djokovic, who committed 51 unforced errors, immediately surrendered the momentum by dropping serve in the first game of the third and he was broken twice more as Davidovich Fokina powered to a 6-3 6-7 (5-7) 6-1 victory in just under three hours.
"I knew that Nole hasn't had that confidence because he didn't play a lot," Davidovich Fokina said.
"This win is so special for me. I look at him every tournament. Here in Monte Carlo, full people [capacity], against the number one, I enjoy every moment."
Earlier, Evans saw off Benjamin Bonzi while Goffin, fresh off his triumph in Marrakech, came through against Jiri Lehecka to set up their second-round meeting.
Tenth seed Taylor Fritz defeated Monegasque wild card Lucas Catarina in three sets and 16th seed Lorenzo Sonego saw off Ilya Ivashka in straight sets. Laslo Djere, a semi-finalist in Marrakech, also progressed to the second round.
The world number one was competing for the first time in five weeks after missing the Indian Wells Open and Miami Open due to being unable to enter the United States.
Djokovic, who has since been cleared to compete in the US Open later this year, faced a spirited challenge from world number 198 Ivan Gakhov but advanced 7-6 (7-5) 6-2.
Gakhov broke his somewhat rusty opponent in the seventh game, but Djokovic hit back instantly as the opening set went to a tie-break.
The Serbian appeared rattled at various points, but an unforced error from Gakhov paved the way for Djokovic to open up some day light and take the opener.
The second set went the way of serve until the fifth game, when a double fault from Gakhov gave his opponent the chance to capitalise and see out the win.
"It was probably, if you can call it this way, an ugly tennis win for me today," Djokovic said in his on-court interview. "I haven't played my best, particularly in the first set.
"And I kind of expected that that was going to happen in a way with swirly conditions, a lot of wind today, changing directions.
"It's different practising and then playing an official match on clay, where I guess no two bounces are the same. It's always quite unpredictable what's going to happen.
"But all in all, I'm just pleased with the way I held my nerves I think in the important moments and I managed to clinch the two-set win."
Defending champion Stefanos Tsitsipas also advanced to the last 16 with a walkover win over Benjamin Bonzi, who retired with a wrist injury when 4-1 down in the opening set.
Fifth seed Andrey Rublev had a tougher time of things against Jaume Munar as he recovered from a set down to progress 4-6 6-2 6-2
Hubert Hurkacz was the other seeded player in action on Tuesday and defeated Jack Draper 6-3 6-7 (7-3) 7-5.
World number 14 Goffin had lost his previous three matches heading to Monaco, but the Belgian delivered a sharp performance on Sunday, winning 6-4 3-6 6-0.
Open Sud de France champion Goffin did not start well, and had to come from 3-0 down in the first set, but Cilic made 52 unforced errors to help his opponent progress.
"It’s a good win. [This is my] first tournament on clay [in 2021]. Starting with a victory is good," said 2017 Monte Carlo semi-finalist Goffin, quoted on the ATP website.
"I did what I needed to do to win that match. I was playing better and better. In the first and second set, I had problems with the returns. In the third set, I was more consistent. It was a good match."
Goffin will face Marco Cecchinato or Dominik Koepfer in the second round, where he has been joined by Australian Jordan Thompson.
Thompson, the world number 62, needed three hours and two tie-breaks to beat Paire 6-4 6-7 (3-7) 7-6 (7-5), as the Frenchman's dismal string of results in 2021 continued.
Paire has now won just one of 10 matches this calendar year, while Thompson registered a fifth win of the season.
A 6-4 7-5 victory for 33rd-ranked Evans in his first career clash with Djokovic carried the Briton through to his first Masters 1000 quarter-final and inflicted a first defeat of 2021 on his opponent.
The seeds of the upset were planted before the players hit the court, Evans later revealed, with the 30-year-old having been irked at having to wait for Djokovic in the locker room.
Top seed Djokovic was playing his first tournament since winning the Australian Open in February, for his 18th grand slam title, and he found it tough against a player who has previously enjoyed little success on clay.
"I thought I did a good job to get out of my service games. He had so many break points but didn't take them, so I was a little lucky there," Evans told Amazon Prime.
"I ran around the first second serve I got, to tell him I'm not going to just stand back and rally, I'm going to try to hit his second serve a little, and I got a few doubles out there."
Djokovic served four double faults, with Evans setting the tone for the match by surging 3-0 ahead early in the opening set.
"He kept me waiting at the start of the match in the changing rooms a little bit, so it was a little annoying," Evans said. "I was ready to go from that, so that got me a little extra fired up."
Rather than being intimidated by the presence of Djokovic on the other side of the net, Evans indicated he treated the Serbian like just another opponent, there to be beaten.
"That's why we roll the balls out, it's one against one and we've got to see who wins," Evans said.
"He gave me some cheap ones today which he never normally does, so I was a little lucky there, but I'm just really happy with coming through."
Evans' win was hailed by former British number one Tim Henman, who said: "He played fantastic tennis. In difficult conditions, he was the one that really dealt with it so well.
"Those first three games where he got up a double break, that probably changed his mindset. It increased his belief and Djokovic was frustrated, but in so many critical moments it was Evans who came up with the great tennis.
"It's an unbelievable achievement. Evans has won so few matches on clay so to beat the world number one, it's an amazing win."
The 22-time grand slam champion has been struggling with a left hip issue that contributed to his second-round exit at the Australian Open in January.
Nadal pulled out of hard-court contests at the Indian Wells Open and Miami Open as he continued to recover from the problem.
Speaking two weeks ago, Monte Carlo Masters director David Massey said Nadal was the first player to register for this year's Masters 1000 event, which begins on April 8.
The tournament's official Twitter account more recently suggested Nadal will "definitely" take part.
However, Nadal – who has slipped out of the world's top 10 men's tennis rankings for the first time in almost 18 years – denied that is the case.
"I don't know who gets this information," he is quoted as saying by Spanish publication Marca.
"Obviously if it were true, I would confirm it, but unfortunately I can't. I'm following my course and I don't know when I'll play again, that's the truth.
"I'm in a phase of increasing work. If I knew when I was going to return, I would say so, but I don't know.
"I can't confirm that I will play in Monte Carlo. Things are seen day by day. I prefer to say things when I really know them."
The Monte Carlo Masters kicks off the clay-court season ahead of events in Madrid and Rome, with the French Open – Nadal's favourite event – now just two months away.
Nadal has won the Monte Carlo Masters a record 11 times, though his most recent triumph came in 2018 with victory over Kei Nishikori in the final.
Karatsev, a surprise Australian Open semi-finalist and a champion in Dubai last month, overcame Lorenzo Musetti, the Italian teenager who was a semi-finalist in Acapulco in March, in straight sets after a four-hour rain delay.
He went into that interruption with a 4-3 lead in the first set and duly polished off the next two games on his return to the court.
The Russian sent down 23 winners as he completed a 6-3 6-4 win in 88 minutes, his last a cross-court backhand that set up a second-round meeting with Stefanos Tsitsipas.
"It was a really tough match [for] my first match of the season on clay [with] tough weather conditions," said Karatsev.
"We started in the morning [and] I started pretty well, I broke him and then the court was getting heavy, the ball was heavy.
"It is tough to play against him. [He is] really fit, [he] runs a lot and gives everything back, so you have to build the point by yourself and close the point by yourself."
There were mixed fortunes for Australians Alex de Minaur and John Millman in Monaco.
De Minaur went down to a surprise straight-sets defeat to Alejandro Davidovich Fokina but Millman broke Ugo Humbert four times in a 6-3 6-3 win.
Next for Millman is either Felix Auger-Aliassime or Cristian Garin, whose first-round contest was among those unable to finish because of the inclement weather on the Cote d'Azur.
Tommy Paul also progressed to the next round, with five matches on court when play was cancelled for the day.
The third seed overcame the Italian 6-3 6-2 to clinch a spot in the round of 16 alongside compatriots Andrey Rublev and Karen Khachanov – marking just the third time in the Open Era that three Russians have reached that stage at Monte Carlo.
Medvedev will face Alexander Zverev, who clinched his spot with a 6-4 6-4 victory over Roberto Bautista Agut earlier in the day, in the next round.
"We've had some tough matches. We played for the first time maybe seven years ago on the ATP Tour, and in juniors maybe 12 years ago," Medvedev said of Zverev.
"I remember I beat him once in a final on clay in juniors, but it’s going to be a different story.
"I saw him in the first two matches, he seemed to be in good shape. I'm just going to have to be at my best."
Elsewhere, Jannik Sinner claimed a 6-0 3-1 victory over Diego Schwartzman, who retired in the second set, to take his total of wins in 2023 to 22, with only Medvedev having more.
There was also a win for Taylor Fritz, who overcame Stan Wawrinka 7-6 (12-10) 6-2, while qualifier Jan-Lennard Struff registered an upset with a 6-3 6-2 victory over Alex de Minaur.
Auger-Aliassime already has one singles title to his name this year, having prevailed in Rotterdam, and also reached the final of the Open 13 in Marseille and helped Canada to victory in the ATP Cup at the start of 2022.
However, the sixth seed entered this contest with just one win from his last four matches and came unstuck once again at the hands of Musetti.
Musetti, who won two sets in the fourth round of the French Open against Novak Djokovic last year, is very much at home on the clay in Monaco.
He demonstrated that in 6-2 7-6 (7-2) success, setting up a last-16 meeting with Diego Schwartzman.
“I live here and practice here,” Musetti said in his on-court interview. "It is nice to be here and play here in front of such a crowd. I am really happy.
"My backhand down the line was a key to many of my great shots. After a really good first set, he came back with such powerful serving, but I was calm and patient and that was the most beautiful thing about today."
Auger-Aliassime's exit came a day after top seed Djokovic was knocked out in the second round by Alejandro Davidovich Fokina, but there were no such problems for second seed Alexander Zverev as he saw off Federico Delbonis in straight sets.
Fifth seed Andrey Rublev came from a set down to defeat Alex de Minaur and fourth seed Casper Ruud, coming off his defeat in the final in Miami, edged qualifier Holger Rune in two tight sets.
The man who vanquished Ruud in Florida will go no further on the Cote d'Azur, however, Carlos Alcaraz losing in just over three hours to Sebastian Korda on his Monte Carlo debut.
Korda lost to Alcaraz in the final of last year's Next Gen ATP Finals, but avenged that defeat with a 7-6 (7-2) 6-7 (5-7) 6-3 victory.
World number 10 Cameron Norrie lost to Albert-Ramos Vinolas and his British compatriot Dan Evans fell to David Goffin, while 16th seed Lorenzo Sonego was beaten by the in-form Laslo Djere.
Elsewhere in the draw, there were wins for Jannik Sinner, Taylor Fritz, Hubert Hurkacz and Pablo Carreno Busta.
Falling to a 4-6 defeat in the first set, Musetti responded to win 7-5 in the second and 6-4 in the third following a rain delay.
The 21-year-old overcame the world number one in a mammoth two-hour, 54 minute encounter and capitalised on weak serves from the Serbian – breaking his opponent eight times en route to a career high victory.
Emotions were high for Musetti, who said afterwards: "I am struggling not to cry. It is an emotional win because it was a really long match. Three-hour match and suspended by rain.
"It was not easy conditions because it was a little bit windy and cold. Not like we used to play in the recent days. I am really proud of myself and I can see on the screen. I am struggling not to cry because it is a dream for me."
Musetti's reward is a clash with Jannik Sinner in the quarter-finals, who trailed Hubert Hurkacz by a set and a break before rallying to a 3-6 7-6 (8-6) 6-1 triumph – sending him into the last-eight in six of the seven events he has played this season.
Elsewhere, Andrey Rublev earned a 50th tour-level win on clay with a 7-6 (6-4) 6-2 victory over Karen Khachanov, who was his doubles partner earlier this week before the pair suffered elimination against Wesley Koolhof and Neal Skupski.
Rublev will meet German qualifier Jan-Lennard Struff in the next round, who secured a major upset earlier in the day by eliminating world number four Casper Ruud.
A 6-1 7-6 (10-8) victory earned Struff his first top 10 win since June 2021, when he defeated Daniil Medvedev in Halle, and advances to his first ATP Masters 1000 quarter-final since Cincinnati in 2020.
The 22-time grand slam champion has been struggling with a left hip issue that contributed to his second round exit at the Australian Open in January.
Nadal pulled out of hard-court contests at the Indian Wells Open and Miami Open as he continued to recover from the problem.
He could return on clay, his favoured surface, with Massey optimistic the 36-year-old will be fit in time to feature at the event, which begins on April 8.
"Rafa was the first [player] to be registered," he said in statement. "He really wants to play at the Monte Carlo Masters.
"He is giving himself every chance to take part in the tournament he's so fond of."
Nadal is the event's all-time record title holder, having triumphed on 11 occasions, with an Open Era record streak of eight consecutive successes between 2005 and 2012.
He last succeeded in 2018, with a straight-sets victory over Kei Nishikori, though various disrupted campaigns have prevented him from mounting another successful bid since.
As a key stop in preparations for the French Open, it has helped form the bedrock of his clay court success over the years.
With this year's event at Roland Garros set to start on May 28, Nadal will be out to add to his 14 singles titles there too, having claimed victory once again in 2022 with a triumph against Casper Ruud in the final.
Nadal, 34, has won the competition more times than anyone else in its history and looked in good shape as he returned to the court for the first time since losing to Stefano Tsitsipas in the Australian Open quarter-finals on February 17.
He needed just 81 minutes to get past the Argentinian qualifier 6-1 6-2 as he improved his record in the tournament to 72-5, breaking Delbonis' serve five times and only dropping his own once.
He is not getting carried away, however, with Grigor Dimitrov likely to provide a sterner test in the next round after beating Jeremy Chardy 7-6 (7-3) 6-4.
"It was solid match, I think. Of course, a very positive result. He's a good player on clay. [It was a] positive start for me," Nadal said in his post-match interview.
"I think I just really played a solid match. Nothing unbelievable, but nothing wrong. Just a solid match, a positive start. I think I did what I had to do."
On Dimitrov, Nadal added: "We've had some great matches. In Melbourne, of course... we played another great match in Beijing, another one in Shanghai. He's a good friend, a good guy, and a great player. It's going to be a tough test in my second round.
"It's going to be his third. I need to be ready for it. I hope to be ready for it. I am just excited to play a tough match very early in the tournament."
A little earlier in the day, world number one Djokovic was in a similarly unforgiving mood as he overcame the potentially tricky obstacle of Jannik Sinner, the Serbian and two-time Monte Carlo champion winning 6-4 6-2.
Like Nadal, Djokovic was back in action for the first time since the Australian Open – which he won – and appeared fresh as he gave the promising young Italian something of a lesson in game management, reaching 10 matches unbeaten at the start of a season for the sixth time.
"It feels great [to be back and] also playing in Monaco, where I reside," Djokovic said. "I have used this club as a training base for almost 15 years, so it feels like playing at home."
Despite the rather commanding nature of his win, Djokovic was keen to pay tribute to the 19-year-old Sinner, adding: "It was a very good encounter. I thought it was a great first match [and] a big challenge for me. Jannik is in form. He played the final [in] Miami and has been playing well. I just hung in there today and managed to find the right shots and the right game at the right time.
"He has got a lot of talent and he has proven that he is the future of our sport. Actually, he is already the present of our sport. He played a final [in an] ATP Masters 1000 [tournament] already. He is making big strides in professional tennis."
Dan Evans awaits Djokovic after an impressive 6-4 6-1 win over Miami champion Hubert Hurkacz, while Alexander Zverez and Andrey Rublev – the fifth and sixth seeds – moved into the next round with respective straight-set victories over Lorenzo Sonego and Salvatore Caruso.
There were mixed fortunes for the other two top-10 seeds in action on Wednesday, as Pablo Carreno-Busta defeated Karen Khachanov 6-2 6-3, but Diego Schwartzman was sent packing by Casper Ruud, the Norwegian winning 6-3 6-3.
Nadal went into the meeting with a 73-5 record at the event but Russian Rublev was in inspired form to stun his Spanish opponent.
The 11-time champion looked set to complete a trademark comeback after taking a 74-minute second set, yet Rublev held firm in the decider to claim a memorable victory after two hours and 33 minutes on court.
"I cannot imagine being in the situation of Rafa, knowing that you are the best player on clay and you have that pressure every time," Rublev said, according to the ATP Tour website.
"I think for him it must be incredibly tough every time. I am in shock [with] the way he is playing under this pressure and that is why he is a legend."
Rublev will face Casper Ruud in Saturday's semi-final after he overcame defending champion Fabio Fognini 6-4 6-3.
Dan Evans followed up his superb victory over Novak Djokovic on Thursday with a slender win over David Goffin to reach his first Masters 1000 semi-final.
World number 33 Evans, who had come into the tournament having lost his previous 10 matches on clay, overcame Goffin 5-7 6-3 6-4 in two hours and 42 minutes.
"I am proud of how I came back today, especially with what happened in the first set," he said after the match.
"I felt my concentration wasn't great and I am really happy with coming through. Yesterday would not have been worth it with a bad performance today."
Evans will face Stefanos Tsitsipas, who progressed when opponent Alejandro Davidovich Fokina retired injured in their quarter-final.
Spaniard Davidovich Fokina did not return for the second set after earlier receiving treatment during the first, which Tsitsipas won 7-5.
Nadal, who has won 11 times in Monte Carlo, had been hoping to make his return from a hip injury at the ATP Masters 1000 event, which starts next week.
The 36-year-old has not played since going out to Mackenzie McDonald in the second round of the Australian Open in January.
Nadal previously cast doubt on his status for Monte Carlo last month, and on Tuesday he announced he will be unable to participate.
"Hi everyone, I'm still not ready to compete at the highest level," Nadal tweeted.
"I will not be able to play in one of the most important tournaments of my career, Monte Carlo.
"I am not yet in a position to play with the maximum guarantees and I continue my preparation process, hoping to return soon."
Nadal's latest setback is another blow in his preparations for the French Open, which starts at the end of May.
The Spaniard, who dominated in Monte Carlo between 2005 and 2012, has slipped down to number 14 in the ATP world rankings.
The 25-year-old Russian has 12 tournament wins to his name, but all have come at ATP 500 or ATP 250 level, respectable but lower rungs than this tier.
Rublev lost to Stefanos Tsitsipas in Monte Carlo in 2021 and to Alexander Zverev in Cincinnati in the same year, as he failed to capitalise on two chances to break his Masters 1000 duck.
Now comes another opportunity on the clay against teenager Rune on Sunday, after both men ground out tough semi-final comeback wins.
Rublev beat Taylor Fritz 5-7 6-1 6-3, while Rune fought back gallantly to overcome Jannik Sinner 1-6 7-5 7-5, with rain delays affected both matches on Saturday.
Rublev is full of appreciation for Rune's game. They met at the last-16 stage of the Australian Open in January, with Rublev winning a marathon clash in a dizzying final-set tie-break.
Their only other previous clash came indoors at the Paris Masters last November, with Rune taking that third-round match in straight sets and going on to win the title as an unseeded player, beating Novak Djokovic in the final.
Rublev said of Rune: "Holger is the guy who runs a lot, and he runs really well. He read the game really well. He's very talented.
"He has a good touch. He doesn't give you any rhythm, because as soon as he has a chance he tries to do drop shots, he tries to hit full power, goes to the net, returns and goes to the net, then serves to the net.
"He doesn't give you rhythm to put pressure on him to play your style."
Rune sees Rublev as a major threat to his prospects of a second title at this level, but the 19-year-old Dane is not short of self-belief.
"I expect for myself to push full. It's the last push, it's the last match of the tournament," Rune said. "Obviously he had three sets as well, so he must be feeling the legs a little bit, I hope.
"It's going to be great. We've played each other twice. It's one-all head to head, so it's going to be interesting, for sure.
"I've just got to stay in the moment, go for it against the best players in the world, and Andrey has been showing that for many years now, he's been top five, six for many years, so I've got to play my best. I've got to take it, because he's not going to give it to me."
Having done the same in his semi-final against Taylor Fritz, Rublev showed grit and determination to do so again in the final, eventually winning 5-7 6-2 7-5.
Rublev become only the third player in the Open Era to have comeback wins in both the semi-final and final at Monte Carlo after Ivan Lendl (1988) and Ilie Nastase (1971).
Rune started the stronger of the two and forced a break in the sixth game of the first set with two delightful drop-shot winners, only for Rublev to break straight back in the next game.
After throwing away seven of eight break point chances in the first set, it was somewhat inevitable Rublev was unable to save a crucial one on his own serve with Rune at set point, sending a return long to hand the Dane the first frame.
This was Rune's sixth ATP Tour-level final, making him the fifth teenager to pass five since 2000.
Rublev seemed determined not to make the same mistake again as he immediately broke Rune's serve in the opening game of the second set, although he did pass up two chances for a double break before Rune levelled the set at 2-2.
The heat appeared to be affecting both players' service games in a high-octane encounter, but Rublev steadied himself before breaking again and then racing to another as he comfortably secured the second set.
As Rublev had done after dropping the opener, however, Rune responded defiantly and raced out to a 3-0 lead in the decider, but after missing a chance to go 5-1 up, he was broken back as Rublev came back to 4-4.
At 5-5, a tiring Rune twice hit the net with overhead smashes and then had a double fault at break point, leading to a crucial break for the Russian, who then served out the match to clinch the title.
"I know it's tough to lose a final, but you are too freaking young, man, and already have a Masters 1000 title, so give me one time to win it," Rublev joked with a smiling Rune at the trophy presentation.
