Mannarino, 34, entered the match with a 1-9 record from his 10 career final appearances, but capped off his incredible week with his fifth consecutive straight-sets win.
On his way to the decider, Mannarino eliminated ninth seed Emil Ruusuvuori, eighth seed Albert Ramos-Vinolas, fourth seed Maxime Cressy and second seed Botic van de Zandschulp.
Against Djere, Mannarino stuck to what he had done all week, which was limiting his own errors and taking advantage of his opponent's mistakes.
The Frenchman committed 12 less unforced errors (29-to-17), while also controlling the game with his serve, winning 78 per cent (49-of-63) of his service points compared to 63 per cent (45-of-71) for Djere.
It was actually the Serbian who secured the first break of the match, but it would also be his last break of the match as Mannarino tightened the screws, not allowing a single break point opportunity in the second set.
With the win, and the 250 ranking points, Mannarino will rise 20 places up to 45th in the world.
Halep, who is the 14th seed after an injury-ravaged 2021, eased past the Montenegrin 6-2 6-1 on Saturday. The former world number one has dropped only 14 games on her way to clinching a spot in the second week in Melbourne.
The Romanian, who was the runner-up at the 2018 Australian Open, won the Melbourne Summer Set 1 title and is re-discovering her best form.
"(This is the best I've played in) the last months," Halep said after Saturday's win.
"I feel great physically, first of all. Mentally I'm confident and also strong, I would say.
"Feeling the game. Feeling joy out there. I think that helps me to be positive and to be confident that I have a chance every time I step on the court.
"I feel I'm in a good spot. I really trust that I can play good tennis here."
Halep will play Frenchwoman Alize Cornet in the fourth round on Monday, with the Romanian having won 11 consecutive sets.
Cornet had knocked out third seed Garbine Muguruza in the second round, while sixth seed Anett Kontaveit and US Open winner Emma Raducanu have also bowed out in Halep's quarter of the draw giving her a good shot at a deep run.
"I feel fresh. I feel that the pressure is off," Halep said. "I feel also that I have expectations from myself, but they are good expectations because I have worked a lot in the off-season.
"I have no injuries. That helps me to be in a good spot mentally and also with confidence."
A battling third-round performance from Frenchman Mannarino sets up a showdown with Rafael Nadal next, and the 33-year-old will hope he has sufficient energy left for that daunting task.
The left-hander clinched victory after four hours and 38 minutes of hard duelling with Karatsev on Margaret Court Arena, with a scattering of fans staying until the bitter end, long enough to hear Mannarino swear during his victory interview.
The watershed in Melbourne had of course long passed by the time Karatsev netted a backhand on match point.
After his 7-6 (7-4) 6-7 (4-7) 7-5 6-4 win, world number 69 Mannarino said: "I was enjoying it, you know. I love rallying, and I was just feeling in shape today, it was pretty cool to play."
But he was aware the match was running well into the early hours, saying: "I realised I was just looking at the clock sometimes, and I was thinking, 'F***'. I don't feel good to be honest'.
"I'm kind of exhausted. But it was cool, and I was so focused on what I had to do. I was not thinking about the fact I was tired.
"I was like, 'Okay, go get the next point'. The crowd was cool. Some people had a couple of drinks, I guess, and were commentating more than anybody."
Mannarino's win took him into the fourth round in Australia for the first time, and it meant he accounted for the 18th seed, a player who won the Sydney Classic last Saturday.
Karatsev reached the semi-finals at Melbourne Park last year as a virtual unknown, before going on to establish himself over the course of the season.
Remarkably, this Friday night into Saturday morning epic was far from the latest finish in Australian Open history, with Lleyton Hewitt having won a five-setter against Marcos Baghdatis at 04:34 local time in 2008.
Nadal continued on his search for a record-breaking 21st grand slam title with the 7-6 (16-14) 6-2 6-2 victory at Rod Laver Arena.
The Spaniard will take on either third seed Alexander Zverev or Canadian 14th seed Denis Shapovalov in the last eight on Tuesday. The win marks Nadal's 14th appearance in the Australian Open quarters.
Nadal has only dropped one set in his first four matches at the Australian Open but the opening set against Mannarino was epic, with the sixth seed edging his opponent after 80 minutes.
The 2009 Australian Open winner trailed 3-0 in the tie-break but fought back to level it up, eventually taking the set 16-14 with his seventh set point.
Nadal assumed complete control from that set on, dominating the second and third to win in two hours and 40 minutes.
The 35-year-old was powerful, sending down 16-7 aces, while he won 88 percent on his first serve across the match. Nadal only offered up two break points for the match.
DATA SLAM: Nadal on the right track
Nadal has dropped 38 games across his four matches at the Australian Open, making light work of Mannarino in the latter two sets which collectively took as long as the first.
The Spaniard won in Melbourne in 2009 but lost finals in 2012, 2014, 2017 and 2019, yet without Novak Djokovic and Roger Federer at this year's event it looms as his best chance for years to lift the title and he seems in good health and form.
WINNERS/UNFORCED ERRORS
Nadal – 42/22
Mannarino – 37/34
ACES/DOUBLE FAULTS
Nadal – 16/6
Mannarino 7/4
BREAK POINTS WON
Nadal – 5/17
Mannarino – 1/2
Nadal continued on his search for a record-breaking 21st grand slam title with the 7-6 (16-14) 6-2 6-2 victory at Rod Laver Arena.
The Spaniard will take on either third seed Alexander Zverev or Canadian Denis Shapovalov in the last eight on Tuesday.
Nadal has only dropped one set in his first four matches at the Australian Open but the opening set against Mannarino was epic, with the sixth seed edging his opponent after 80 minutes.
The 2009 Australian Open winner trailed 3-0 in the tie-break but fought back to level it up, eventually taking the set 16-14 with his seventh set point.
Nadal assumed complete control from that set on, dominating the second and third to win in two hours and 40 minutes.
The 35-year-old was powerful, sending down 16-7 aces, while he won 88 percent on his first serve across the match. Nadal only offered up two break points for the match.
DATA SLAM: Nadal on the right track
Nadal has dropped 38 games across his four matches at the Australian Open, making light work of Mannarino in the latter two sets which collectively took as long as the first.
The Spaniard won in Melbourne in 2009 but lost finals in 2012, 2014, 2017 and 2019, yet without Novak Djokovic and Roger Federer at this year's event it looms as his best chance for years to lift the title and he seems in good health and form.
WINNERS/UNFORCED ERRORS
Nadal – 42/22
Mannarino – 37/34
ACES/DOUBLE FAULTS
Nadal – 16/6
Mannarino 7/4
BREAK POINTS WON
Nadal – 5/17
Mannarino – 1/2
Van de Zandschulp, the second seed, is yet to lose a set in the tournament after straight sets wins against Tallon Griekspoor and Jaume Munar, and he used his dominant serve to get the job done against France's Bonzi.
The Dutchman had 15 aces while Bonzi had three, and he posted 50 winners to Bonzi's 24 in a terrific exhibition of power tennis.
Van de Zandschulp, 26, will face Adrian Mannarino in the semi-final as the 34-year-old seeks his second career ATP Tour title, beating Maxime Cressy 6-4 7-6 (7-3).
Fourth seed Cressy was Mannarino's third consecutive seeded scalp, having also defeated ninth seed Emil Ruusuvuori and eighth seed Albert Ramos-Vinolas to make it this far.
Cressy's 10 double faults and 26 unforced errors shot himself in the foot, as the veteran Mannarino played a clean match, posting two double faults and eight unforced errors.
Serbia's Laslo Djere has taken the scenic route to the semi-final, winning his fourth three-set match of the week as he edged past Richard Gasquet 6-4 3-6 7-6 (8-6) in two hours and 43 minutes.
It comes after a three-hour-11-minute marathon against Jason Kubler in the previous round, and a two-hour-50-minute war of attrition against Joao Sousa prior to that.
Djere will hope to have some more gas in the tank when he meets Switzerland's Marc-Andrea Huesler in the semi-final after he upset 13th seed Jack Draper 6-4 6-4.
This has been a tough season for the Australian, who had not managed to wins at the same Tour-level event since the Australian Open until this week.
But a string of impressive results against Fernando Verdasco, Tommy Paul and then Frances Tiafoe secured a final meeting with Mannarino.
The Frenchman's 2020 struggles have been even more stark, taking a 6-14 record to Kazakhstan, and he proved an accommodating opponent for Millman, failing to take his opportunities.
Five break points came and went for Mannarino in the first set before Millman broke at the first attempt to take the opener.
Mannarino then offered little resistance in the second, waiting until the final game to squander his sixth and last chance as Millman claimed a straight-sets win.
The Belarusian saw off Aljaz Bedene, with a 6-4 7-6 (7-4) win carrying him through to the quarter-finals of the Open Sud de France.
Bedene was British number two to Murray heading into Wimbledon in 2016, when the Scot won his third grand slam title, but has since reverted to representing his native Slovenia.
He put up a fight against Gerasimov, who sank Murray in straight sets on Tuesday, but the 28-year-old from Minsk took three of his five break-point opportunities and held his nerve in the tie-break to advance.
The success for Gerasimov sets up a last-eight clash with Spain's Alejandro Davidovich Fokina, who scored a fine 7-5 6-2 win over Polish fourth seed Hubert Hurkacz.
Top seed and world number 13 Roberto Bautista Agut raced to a 6-0 6-3 victory over French qualifier Gregoire Barrere, but Croatian third seed Dusan Lajovic tumbled out, losing to Dennis Novak in straight sets.
At the Singapore Open, second seed John Millman fell by the wayside, the Australian slumping 6-4 6-1 to compatriot Matthew Ebden.
French top seed Adrian Mannarino encountered no such problems, ending the hopes of Roberto Marcora with a 6-3 7-5 win to join Ebden in the quarter-finals.
The Belgian lost both matches at the inaugural United Cup last week, but he saw off Bublik 6-3 6-4 in 74 minutes to reach the last 16 in New Zealand.
Another seeded player fell at the first hurdle on Monday as Adrian Mannarino lost 6-4 7-6 (7-4) to J.J. Wolf.
Richard Gasquet advanced with a 6-3 6-1 win over wild card Kiranpal Pannu, while Jenson Brooksby beat Fabio Fognini 6-7 (2-7) 6-1 6-3 and will now face Diego Schwartzman.
At the Adelaide International 2, fifth seed Dan Evans suffered a 7-5 7-5 defeat to Mackenzie McDonald.
Fellow seeds Alejandro Davidovich Fokina and Miomir Kecmanovic overcame Brandon Nakashima and Kyle Edmund respectively.
Fifth seed Auger-Aliassime was taken out 6-2 7-5 in one of the biggest wins of Francisco Cerundolo's career, with the Argentine avenging recent losses to the Canadian at both the Australian Open and the Indian Wells Open.
Adrian Mannarino's 7-6 (7-5) 7-6 (7-0) victory over eighth seed Hurkacz was arguably an even bigger upset, as it snapped his streak of nine consecutive losses against top-10 opponents at Masters 1000 events.
The 34-year-old Frenchman absorbed 20 aces from Hurkacz and still came out on top, limiting his own unforced errors to 13 for the match.
A third upset of the day saw unseeded Italian Lorenzo Sonego play a near faultless match to eliminate 12th seed Tiafoe, finishing the contest with 22 winners and only two unforced errors, while not facing a single break point in the brief 68-minute battle.
There was no drama for Daniil Medvedev as the fourth seed received a walkover against Alex Molcan, and he will face France's Quentin Halys in the fourth round after his 7-6 (7-2) 6-3 triumph over Mackenzie McDonald.
Two seed Stefanos Tsitsipas almost joined the long list of seeded victims, but he prevailed 6-3 4-6 6-4 against Christian Garin in the day's only three-setter.
The Greek star will meet Russian 14th seed Karen Khachanov in the fourth round after his comfortable 6-2 6-4 result over Jiri Lehecka, while unseeded American Christopher Eubanks finished the day's play with a 6-3 7-6 (9-7) defeat of Gregoire Barrere.
Hurkacz made it through a tough encounter against Stan Wawrinka 7-6 (7-5) 6-4 to give Poland a 2-1 lead in their Group B tie with Switzerland in Brisbane, before Linette came from behind to beat Jil Teichmann 5-7 6-4 6-1 to clinch it.
Poland will face Italy in the Brisbane final, whose 5-0 whitewash of Norway included Matteo Berrettini sealing victory with a 6-4 6-4 win over Casper Ruud.
In Perth, Croatia advanced to the City Finals after a dramatic day that saw Caroline Garcia get France on the board with a straight sets win against Petra Martic, before Adrian Mannarino came from a set down against Borna Gojo to serve for the match as he looked to bring his country level at 2-2.
However, Gojo broke back in a tense encounter before winning a deciding tie-break to send Croatia through to face Greece, who sealed a 4-1 win against Belgium.
Stefanos Sakellaridis recovered from going a set behind to beat Zizou Bergs, before Maria Sakkari overcame Elise Mertens 6-1 7-5, with Sakkari and Stefanos Tsitsipas adding some gloss to the score with a mixed doubles success against Kirsten Flipkens and Michael Geerts.
Spain and Australia were unable to progress but the hosts at least had the consolation of securing a victory thanks to wins for Jason Kubler against Albert Ramos-Vinolas, and the mixed doubles duo of John Peers and Sam Stosur against Jessica Bouzas Maneiro and David Vega Hernandez.
The USA had already secured their Finals berth against Great Britain in Sydney, but were ruthless as they finished off their tie against Germany to win 5-0.
After Jessica Pegula beat Laura Siegemund 6-3 6-2, Frances Tiafoe also defeated Oscar Otte in straight sets, before the American duo combined to beat Siegemund and Daniel Altmaier 6-7 (5-7) 6-4 10-7 to complete a clean sweep.
A day on from beating Feliciano Lopez for his 1,000th ATP Tour-level victory, Nadal saw off Jordan Thompson in straight sets on Thursday.
The Spaniard lost just 12 points on his serve in his first meeting with world number 61 Thompson, who hauled down his racket after failing to win a set point in the second, which Nadal subsequently won on a tie-break.
Yet despite another impressive showing in Bercy, Nadal believes he still has work to do if he is to overcome compatriot Busta, who beat Norbert Gombos 7-5 6-2.
"I want to improve everything, always," the world number two said after his 6-1 7-6 (7-3) triumph. "But that's the work of every day, no? Try to fix the things that I think I can do it better, and hold the things that I am doing well, no?
"So I think I am not doing a lot of things bad. I just didn't play in indoors for a year almost, and is part of the process of course. I need to keep going. I think these kind of matches helps. Yesterday's match, today's, tomorrow is another opportunity.
"These matches are an important test for me to keep improving, so I really believe and hope that it's going to help me to improve. I think I'm playing well. I just think I need to win more matches on this surface.
"I need to be ready to play my best against an opponent that I know is playing well and with confidence. I hope to be ready to play my game and really read well, because that's what I'm going to need."
WAWRINKA AND ZVEREV BATTLE THROUGH
Nadal is into the Paris Masters quarters for an eighth time but the 34-year-old has only reached the final on one previous occasion, losing to David Nalbandian in 2007.
Should he overcome his compatriot Busta on Friday, one of Alexander Zverev or Stan Wawrinka await in the semi-finals.
Fourth-seeded Zverev needed three hours to overcome unseeded Adrian Mannarino 7-6 (13-11) 6-7 6-4, saving set points in each of the first two sets.
Zverev wasted a set point of his own in a tie-breaker as the German was taken all the way to a decider, which he won by breaking Mannarino in the ninth game.
Chasing a third title of the year, Zverev will now face Wawrinka in the last eight after the Swiss battled from behind to beat Andrey Rublev 1-6 6-4 6-3.
Rublev broke his opponent three times to take the first set inside 32 minutes, but Wawrinka held in the second to level up a match that went on past midnight local time.
World number eight Rublev had won 11 matches in a row but he struggled to cope with Wawrinka in the third set, losing serve in the first and ninth games to bring his participation to an end.
Zverev was crowned Cologne Indoors champion last weekend and the US Open runner-up moved into the quarter-finals of the Cologne Championships on Wednesday.
The top seed beat Australian Millman 6-0 3-6 6-3, despite double-faulting 10 times, and has now won 11 of his last 12 matches on hard courts.
Zverev saved six of the seven break points Millman earned and won 79 per cent of points behind his first serve, setting up a last-eight meeting with eighth seed Adrian Mannarino.
Mannarino was a 6-3 6-3 winner against Miomir Kecmanovic, while Alejandro Davidovich Fokina advanced to the quarter-finals following a 7-6 (7-3) 6-3 victory over Steve Johnson.
Felix Auger-Aliassime, beaten by Zverev in the final on Sunday, rallied past qualifier Egor Gerasimov 4-6 7-6 (7-2) 7-6 (7-4).
Pablo Carreno Busta slumped to a surprise defeat at the European Open in Antwerp, Ugo Humbert beating the second seed 5-7 6-3 6-4.
Frenchman Humbert was joined in the quarter-finals by Grigor Dimitrov, Alex De Minaur and Dan Evans, while Milos Raonic and Taylor Fritz progressed to the round of 16.
Isner, 37, relied as he usually does on his trusty serve to get the job done in tiebreakers, winning the match despite not breaking Shelton's serve a single time.
The second seed won 85 per cent (60-of-71) of his successful first serves, while Shelton was similarly stout, converting 83 per cent (50-of-60).
Isner will meet fellow American Jenson Brooksby in the quarter-finals after he came back from an early break to defeat Mackenzie McDonald 6-3 6-4.
The biggest differentiating factor between the two players was Brooksby's effectiveness off his second serve, winning 61 per cent (14-of-23) of those opportunities compared to just 22 per cent (four-of-18) from McDonald.
Fourth seed Alex de Minaur defeated fellow Australian James Duckworth 6-4 6-4 in a competitive match, but De Minaur simply created more chances for himself, with five break point opportunities while Duckworth had two.
De Minaur will play France's Adrian Mannarino after he defeated American Andres Martin 7-5 6-3.
Mannarino's main advantage was with his return game, securing four breaks of serve while dropping his own serve only once.
Van de Zandschulp, the tournament's second seed, was the last seeded entrant remaining in the draw.
In a dominant first set, Mannarino won 80 per cent (12-of-15) of his service points to not allow his Dutch opponent any openings, and he took advantage of some sloppy play.
Van de Zandschulp committed four double faults and 16 unforced errors in the opening set, while Mannarino had no double faults and only one unforced error as the 34-year-old played a veteran's game and allowed his opponent to beat himself.
Overall, Van de Zandschulp committed 20 more unforced errors and five more double faults in the loss.
Mannarino will play Serbia's Laslo Djere in the final, with a chance to win his second career ATP Tour title. His sole title came at the Netherlands' Rosmalen Championships back in 2019. He has a career record of 1-9 in finals.
Djere made it through after yet another grinding affair, defeating Switzerland's Marc-Andrea Huesler 7-6 (7-3) 7-6 (7-5) in two hours and 20 minutes.
All five of his wins this week have required over two hours of court time, with this being his first straight sets result.
In a match that saw each player secure one break of serve, Djere was just slightly better throughout, winning 52 per cent (98-of-189) of the total points, while building a 37-24 advantage in the winners category and serving 10 aces to Huesler's four.
The seventh-seeded Frenchman, knocked out by Aljaz Bedene in the first round at Roland Garros, was beaten 6-3 6-2 by a player ranked 65 places lower than him, with Duckworth outside the world's top 100.
Home hopes Yannick Hanfmann and Peter Gojowczyk progressed, the latter coming from a set down to beat Ilya Ivashka 5-7 6-4 6-2, but there was no such joy for fellow German Dominik Koepfer after he fell to wildcard Jurij Rodionov.
Elsewhere in the draw, there were wins for Feliciano Lopez, Sam Querrey, Dominic Stephan Stricker and Jordan Thompson.
Mannarino secured a 7-6 (9-7) 6-4 win on Sunday to reach the second round in his homeland.
The Frenchman roared back from 5-1 down in the first set and rocked Karatsev further by winning the tie-break.
Mannarino then claimed the only break of the second set to advance at the expense of the Russian.
Holger Rune will be his opponent in round two following the Dane's 7-6 (7-4) 7-6 (7-3) defeat of Arthur Rinderknech.
Francisco Cerundolo will do battle with top seed Cameron Norrie in the second round after the Argentine saw off James Duckworth 6-2 3-6 6-3.
There were just two matches in the first round of the Geneva Open, with Tallon Griekspoor and Kamil Majchrzak progressing at the expense of seeds Tommy Paul (6) and Alexander Bublik (8) respectively.
One of the top seeds in action, Giron is ranked over 300 spots higher than Rybakov, but the underdog put up a serious fight and held up well in all key indicators.
Rybakov had 29 winners with only 17 unforced errors, and he had just two double faults to go with seven aces, but Giron was better in both categories. His talent shone through with 34 winners and 16 unforced errors, while he also had 10 aces and no double faults.
Also in Dallas, French eighth seed Adrian Mannarino secured a 7-6 (8-6) 6-2 win against Steve Johnson, and he will now face Australia's Jordan Thompson following his 6-1 7-5 triumph over Denis Kudla.
Meanwhile, at the Cordoba Open, Argentina's Federico Coria was the top seed to advance after defeating Brazil's Thiago Monteiro 6-7 (5-7) 6-1 6-2.
There was less success for hometown seventh seed Pedro Martinez, who was eliminated 7-6 (7-3) 2-6 6-0 by Chile's Cristian Garin, while Federico Delbonis beat Alejandro Tabilo 6-7 (8-10) 6-2 7-6 (8-6) to earn a shot at second seed Francisco Cerundolo.
Defending champion Mannarino had won eight matches in a row at the ATP 250 event, which was last held in 2019, but he fell 7-5 7-5 to Medvedev in a match lasting a little under two hours.
Top seed Medvedev, whose most recent appearance in a final came at the Australian Open in January, will now face home favourite Tim van Rijthoven on Sunday.
"Adrian plays good, and some games in this match I was like: okay, I can't do anything," said Medvedev, who will reclaim top spot in the ATP rankings next week.
"I had to just continue playing my tennis. He was unbelievable sometimes, missing sometimes, so I just continued my game, and it managed to work today."
Medvedev was far from his best against flat-hitting Mannarino, with the first set featuring five breaks of serve, but the 26-year-old did enough to edge in front.
After wasting a chance to serve out the match in the 10th game of the second set, Medvedev edged a mammoth 11th game and avoided any sort of scare to advance through.
The Russian will next face a different sort of test against Van Rijthoven after the Dutch wildcard stunned second seed Felix Auger-Aliassime earlier on Saturday.
Van Rijthoven, who had not won a match at tour level until his opening-round win over Matthew Ebden, prevailed 6-3 1-6 7-6 (7-5) in a thrilling semi-final.
After sharing the first two sets, Van Rijthoven wasted six break-point opportunities in the decider, but he held his nerve in the tie-break to keep his dream run going.
He is the first Dutchman to reach the final in 's-Hertogenbosch since Raemon Sluiter in 2009.
Murray, a five-time champion at Queen's, was beaten 6-3 6-3 by Italian Berrettini as the three-time grand slam champion struggled a day on from being given a Wimbledon wildcard.
The former world number one beat Benoit Paire in his first ATP Tour singles match since March on Tuesday, but the 34-year-old revealed he is still being troubled by a groin injury after his loss to Berrettini and knows he must raise his game.
Murray said: "I actually felt my movement was actually quite good for both of the matches. My tennis today was not very good. That's the thing that I'll need to improve the most.
"Then there is still a slight niggle in the groin, so [I have] to try to get rid of that discomfort between now and Wimbledon. I need to be playing points, basically. I played two sets in preparation for this event.
"I do feel like I genuinely have been hitting the ball well in practice, but then like today when you're under a bit more pressure and stuff and you're having to make very split-second decisions when you're on the court, if the guy is serving 140 miles an hour, like, it's difficult to prepare for that."
Dan Evans made history earlier in the day, getting the better of Adrian Mannarino 6-4 7-6 (9-7).
With Jack Draper and Cameron Norrie having already progressed, Evans' win ensured there will be three Britons in the singles quarter-finals for the first time in the Open Era.
Feliciano Lopez will not retain his title in London after the Spaniard went down 6-2 6-3 to second seed Denis Shapovalov. Spanish veteran Lopez won in 2019, with last year's tournament cancelled due to the pandemic.
There will be no glory on home soil in Halle for German Zverev, who was taken out 7-6 (7-4) 3-6 6-3 by unseeded Frenchman Humbert.
Humbert has now beaten a top-10 player on every surface, with Zverev serving 20 aces but bowing out after his 22-year-old opponent claimed the only break of the final set.
Sebastian Korda battled past Kei Nishikori 2-6 6-3 7-5 in Halle, while Lloyd Harris also moved into the last eight at Lukas Lacko's expense.
