Opelka kept up his strong early-season form with an imposing 6-3 7-5 victory over Nick Kyrgios in the first semi-final, getting the job done in just one hour and nine minutes.
Opelka slung down 18 aces to 11 from Kyrgios and faced only one break point across the contest.
The 24-year-old Opelka won a title in Dallas in February and followed up with a run to the Delray Beach final, with a third trophy match of the season now awaiting him.
The American world number 18 said he admired the "intangibles" from Kyrgios that "you can't teach."
"He's got one of the best serves in the world and when he turns it on he can come up with some shots that not many guys outside the top 10 can," Opelka said in his on-court interview.
Opelka enjoyed the high-tempo match with Kyrgios, who typically wastes no time between points.
"I prefer to play at that speed rather than, for example, Rafa [Nadal] where it's 50-55 seconds between points," Opelka said.
"It's a totally different speed here and I thought I did a good job managing the whole tempo of the match. I put a lot of returns into play and I came up big with my second serve."
He will face 2013 Houston champion Isner, who came from a set down to defeat defending champion Cristian Garin 4-6 6-3 6-4.
The 36-year-old's serve improved as the match went on and ultimately propelled him to victory, facing four break points in the opening set, one in the second and none in the decider.
Isner also served 17 aces on his way to the final, and won 80 per cent of points on his first serve.
"It's never easy when you have to come back from one set down," he said. "My serve certainly helped me out a lot. I didn't have to hit too many balls there in the end, and I didn't want to.
"I'm so happy to be in the final again here. At my age you never really know when you can get back to a final of a tournament like this."
In a battle between two of the United States' brightest young men's tennis talents, neither could find a way to break the other's serve.
That meant it came down to the shoot-out of the tie-break in each set, with Opelka sealing a 7-6 (7-5) 7-6 (7-3) victory in an hour and 51 minutes.
It gives the world number 23 a third ATP title of his career, all of which have been won in America. His previous successes came at Delray Beach and the New York Open.
This indoor showpiece on Sunday was just a second main-tour final for 54th-ranked Brooksby, a player who caught the eye in a breakout 2021 campaign, and he found Opelka's serve impenetrable, as has been the case for all-comers throughout the week.
Opelka faced just one break point in the title match, the first against his serve all week, but staved that off. He had five chances against the Brooksby serve but could also not take advantage.
Rather than power, Opelka finished off the match with finesse, hitting a backhand winner after a teasing exchange. He then described 21-year-old Brooksby as "a future top-10 player" after keeping the youngster waiting for his first ATP title.
Brooksby was ranked outside the top 300 this time last year and is poised for a first top-50 breakthrough.
The champion was delighted with his own game, with Opelka saying at the trophy presentation: "I thought I played very well under pressure, especially against a great player like Jenson.
"He makes you very uncomfortable and he took me out of my comfort zone a lot of the match today. I really had to play my best tennis to get by and I barely did."
Tommy Paul beat fellow American Reilly Opelka at the Dallas Open to reach the semi-finals of the tournament, while Casper Ruud also won.
The world number eight triumphed in Switzerland 12 months ago with victory over Denis Shapovalov in the final, claiming the first of five ATP titles he won during an impressive campaign.
Fresh from reaching the semi-finals in Rome, the Norwegian – also a winner in Buenos Aires and a Miami runner-up this season – made a dominant start.
Although he was broken in game three of the opening set, Ruud responded immediately and a further four breaks wrapped up a commanding 6-3 6-1 victory in just 55 minutes.
Meanwhile, Reilly Opelka registered his first win on European clay this season as he saw off Christopher O'Connell.
Despite triumphing in Dallas and Houston earlier this year, Opelka has suffered first-round exits in Munich, Madrid and Rome since the latter.
Nevertheless, the fourth seed was in fine form in Geneva, hitting 13 aces on the way to defeating the Australian qualifier.
However, there was no joy for 2021 runner-up Shapovalov as the third seed crashed out 6-4 6-7(2) 6-3 to Ilya Ivashka.
Fifth seed Nikoloz Basilashvili fell 6-4 6-3 at the hands of 2015 finalist Joao Sousa, who progresses beyond round two for the first time since reaching the Championship match seven years ago.
There were more surprise defeats in Lyon, where second seed Pablo Carreno Busta was beaten 7-5 6-3 by Federico Coria.
After taking a close opening set, the world number 59 rallied from 3-1 down in the second to reach his fourth quarter-final of the season on clay.
Karen Khachanov also bowed out to Marrakech runner-up Alex Molcan 6-2 7-6(4), while Munich champion Holger Rune built on his momentum with a 6-4 6-3 victory over Adrian Mannarino.
The giant American, who measures in at six-foot-11, was terrific in the opening set, winning 84 per cent of his successful first serves (16-19) and allowing no break point opportunities.
The second set was much more competitive, as Brouwer broke first to go up 3-1, but Opelka answered instantly and then grabbed the match-winning break when 6-5 up to avoid a tie-breaker.
Opelka will face a fresh Nick Kyrgios in the semi-final after the Australian was gifted a walkover win against Michael Mmoh due to injury.
In a clash between two top-five seeds, world number 29 Christian Garin got the better of world number 13 Taylor Fritz 6-2 6-7 (5-7) 6-3.
What made Garin successful in the first and third sets was his return game, winning more than half of his return points in those sets combined (26-51).
Fritz had chances to get back into the game, but Garin saved 11 of 14 break point opportunities, including six of seven in the deciding third set.
Garin will play American John Isner in the semi-final after Isner triumphed in a three-set battle against Frances Tiafoe 6-4 2-6 6-3.
Isner's trademark serve was inconsistent, and abandoned him in a grim second-set performance, winning just 11 of 21 service points on his way to getting broken twice to allow Tiafoe to force the match into a third frame.
In Isner's two successful sets, he won more than 80 per cent of his first serves (35-41), and allowed no break point opportunities in the third.
Tommy Paul took down Rublev, beating the fourth seed for the first time in four meetings, while the ninth-seeded Shapovalov fell to Aslan Karatsev.
The news was not all bad for the higher seeds, though, as US Open champion Medvedev picked up his 50th win of the year.
PAUL DOWNS RUBLEV
Playing in the main draw at Indian Wells for the first time, the 24-year-old American Paul outlasted Rublev 6-4 3-6 7-5 for his second win in eight career matches against top-10 players.
Paul was on the offensive throughout the match, firing 41 winners while making 37 unforced errors, while Rublev had 23 of each.
The Russian will lament missed opportunities, as he converted just four of 14 break point chances before watching Paul break him twice in the final set to prevail.
Paul moves on to face 21st seed Cameron Norrie, who beat Roberto Bautista Agut 6-4 5-7 6-3.
MEDVEDEV NOTCHES 50TH WIN
Medvedev had to work a bit to get past 27th seed Filip Krajinovic 6-2 7-6 (7-1), improving to 38-5 on hard courts in 2021. Only Stefanos Tsitsipas (52) has more victories overall this year.
The Russian had 25 winners and 18 unforced errors while winning 70 per cent of points on his first serve.
He next faces 23rd seed Grigor Dimitrov, who downed 16th seed Reilly Opelka 6-3 6-4.
KARATSEV UPSETS SHAPOVALOV
Playing at Indian Wells for the first time, 19th seed Karatsev upset Shapovalov 7-5 6-2, saving the only break point he faced in the match.
Casper Ruud, seeded sixth, rallied past Lloyd Harris 6-7 (4-7) 6-4 6-4 as he seeks his sixth tournament title this year.
He will face 11th seed Diego Schwartzmann, who beat 18th seed Daniel Evans 5-7 6-4 6-0 to reach the fourth round at Indian Wells for the first time.
Eighth seed Hubert Hurkacz had little trouble with Frances Tiafoe, rolling past the American in straight sets.
Jannik Sinner, the 10th seed, advanced via walkover when John Isner withdrew from the tournament to fly home and be with his wife Madison with their third child expected to arrive ahead of schedule on Tuesday.
Andrey Rublev was a surprise first-round loser at the Halle Open, while numerous seeds fell on the first day of the Queen's Club Championships.
Rublev came unstuck against Georgian Nikoloz Basilashvili, succumbing to a 7-6 (7-1) 6-4 loss as the world number eight crashed out in Germany.
Laslo Djere progressed after Henri Squire retired when 4-3 down, while sixth seed Pablo Carreno Busta secured a 6-3 7-6 (7-5) over French Open quarter-finalist Holger Rune.
Ugo Humber got the better of a topsy-turvy affair against qualifier Radu Albot, eventually triumphing 6-7 (4-7) 7-6 (7-4) 7-5 and Mackenzie McDonald defeated Marc-Andrea Huesler in straight sets.
Fourth favourite Taylor Fritz went down 6-3 6-3 against British wildcard Jack Draper, his first career win against a top-20 ranked player.
Reilly Opelka, the eighth seed, crashed out in the first round to New Zealand's Alex de Minaur, who claimed a straightforward 6-4 6-4 win.
Grigor Dimitrov, who won the event in 2014, battled past third seed Cameron Norrie 6-7 (2-7) 6-1 6-4, while Spaniard Alejandro Davidovich Fokina eased past compatriot Albert Ramos-Vinolas 7-5 6-4.
Alexander Bublik was 6-3 up before Italian Lorenzo Musetti retired, while seventh seed Marin Cilic capped the day's play in London by beating home hope Liam Broady 6-1 4-6 7-5.
World number nine Ruud was a 7-6 (7-2) 7-5 winner against Reilly Opelka on Friday, putting him on the brink of a second ATP Tour crown of the season and a sixth in his past seven ATP 250 events on clay.
The Norwegian made the semi-finals at the Internazionali d'Italia last week and maintained his momentum ahead of the French Open.
He converted the match's only breakpoint in the penultimate game and sealed the deal in the next, dropping just five of 46 points behind his first serve throughout.
Ruud will take on Joao Sousa – who was the runner-up to Thomaz Bellucci in Geneva seven years ago – in the final after the Portuguese defeated Richard Gasquet 6-2 6-2.
Norrie will also be hopeful of making up for a past final defeat after winning his last-four encounter with Holger Rune at the Lyon Open.
The Briton was a set and a break up before Rune recovered to force a decider, which Norrie took for a 6-2 5-7 6-4 triumph in a little over two hours.
Norrie was beaten by Stefanos Tsitsipas in last year's final but it is Alex Molcan who stands between him and the trophy this time around.
Molcan, who is yet to win a Tour-level title, claimed an impressive victory 7-6 (7-2) 6-2 win over Alex de Minaur.
World number eight Rudd, who claimed the title in Geneva last year with a straight-sets final win over Denis Shapovalov, overcame Kokkinakis 6-4 7-6 (7-3) on Thursday and will now face Opelka.
The American bounced back from losing the second set against Dutchman Tallon Griekspoor to claim a 6-4 3-6 6-3 win as he bids for his third title of 2022, and second seed Ruud said he was excited to pit himself against Opelka after securing his spot in the semi-finals.
"I expect it to be tough," Ruud said. "But I will do my best and see how I can do. I always enjoy playing against Reilly. He is a similar age to myself, and it will be another battle against him – hopefully it will be a good one."
Elsewhere, three-time grand slam semi-finalist Richard Gasquet followed up his shock win over Daniil Medvedev with a 6-2 6-4 victory over Kamil Majchrzak, and will face Joao Sousa for a place in the final after the Portuguese beat Ilya Ivashka 7-5 7-5.
At the Lyon Open, top seed Norrie battled to a 6-4 4-6 7-5 win over Sebastian Baez, spurning three match points before finally downing the Argentinian after a marathon two hours and 40 minutes clash.
The world number 11 will face Holger Rune in his semi-final contest after the 19-year-old came from a set down to beat Manuel Guinard 3-6 6-3 6-4.
The other semi-final in France will see fourth seed Alex de Minaur take on Alex Molcan after the Australian's quarter-final opponent Yosuke Watanuki withdrew after losing the first set 6-4, citing a back issue.
Molcan, meanwhile, downed Federico Coria 6-3 6-2 to reach the final four.
The Argentine world number 14 had to overcome countryman Francisco Cerundolo 6-3 2-6 5-7 earlier on Saturday after their quarter-final had been interrupted by rain on Friday evening.
The match was tied at 1-1 in the third set when rain intervened, with Schwartzman triumphing when play resumed to earn a semi-final date with third seed Lorenzo Sonego.
Schwartzman would later beat Sonego 7-5 3-6 6-2 in almost three hours on a busy day for the 2020 French Open semi-finalist.
World number eight Ruud progressed with a routine 6-3 6-3 victory over Argentine sixth seed Federico Delbonis.
At the Dallas Open semi-finals, Reilly Opelka and John Isner broke the record for the longest tiebreaker on the ATP Tour since 1990.
Second seed Opelka triumphed over fellow American Isner but it was not easy, winning 7-6 (9-7) 7-6 (24-22).
Opelka sent down 39-21 aces across the match, earning a spot in the final against fourth seed Jenson Brooksby who beat Marcos Giron 6-4 6-7 (4-7) 7-6 (7-5).
Sinner won his fourth title of what has been an outstanding season for the Italian in Antwerp last weekend and is only 110 points adrift of Hubert Hurkacz in the battle for the final place in the season-ending event in Turin.
Murray did the 20-year-old a favour by knocking Hurkacz out of the ATP 500 tournament in the Austrian capital on Monday and seventh seed Sinner eased to a 6-4 6-2 win over American Opelka two days later.
Sinner, who will overtake Pole Hurkacz if he reaches the semi-finals this week, won 93 per cent of points behind his first serve and did not face a break point in a resounding win and will play Dennis Novak in the second round.
Murray beat Alcaraz at Indian Wells this month, but the 18-year-old rising star from Spain turned the tables on the three-time grand slam champion with a 6-3 6-4 second-round win in Vienna.
Former world number one Murray struggled with his serve and was broken five times as he made an early exit.
Third seed Matteo Berrettini beat Nikoloz Basilashvili 6-7 (5-7) 6-2 6-3 to reach the third round, while Diego Schwartzman, Gael Monfils and Lorenzo Sonego moved into the second round.
In the St Petersburg Open, defending champion Andrey Rublev beat Ilya Ivashka 6-4 6-4 to reach the quarter-finals along with Denis Shapovalov, a 2-6 6-3 6-0 winner against Pablo Andujar.
Jan-Lennard Struff also moved into the last eight, with Karen Khachanov and Marin Cilic securing first-round wins.
In a clash between two of the tour's elite servers, and two of the tallest men to ever play professional tennis, break points were hard to come by, and even harder to convert, as Opelka saved all eight opportunities he faced, while Isner saved four out of five.
That one break decided the first set, as 6ft 10in Isner fought back from 40-0 down to force deuce, but the fourth break point of the game was converted by 6ft 11in rival Opelka.
The ATP said their respective heights made it the tallest tour final in the Open Era.
In a match that was always likely to be decided by whoever served best, Opelka had five aces to Isner's two in the first set, while Isner also had the only double fault.
Isner was much stronger in the second set, creating seven break-point opportunities, but he just could not win the important points as Opelka's serve repeatedly got him out of trouble.
Isner then had three opportunities at set point in the tie-break to force a decider, but it was Opelka's day, as he saved all three and converted his first chance at match point.
After dropping a set in his first-round match against Mitchell Krueger, Opelka was perfect the rest of the tournament, beating Gijs Brouwer and Nick Kyrgios in straight sets on his way to the final.
Three-time grand slam champion Wawrinka, whose most recent major success came at the 2016 US Open, was competing in just his second ATP Tour match in 14 months after recovering from a foot injury but battled past American Opelka 3-6 7-5 6-2 in Rome.
Opelka seemed to hold the initiative after dominating the first set and boasting a 4-2 advantage in the second, but the 37-year-old Swiss recovered well to fight back against the world number 17.
Wawrinka managed to release his heavy-hitting forehand and close the court by nearer to the net, with Opelka providing no response as the former world number three triumphed in two hours and five minutes.
Laslo Djere or Borna Coric will be the second-round opponent for Wawrinka, who registered his first tour-level win since February 2021.
Before defeating Opelka, Wawrinka had not won a match since he defeated Pedro Sousa at the Australian Open last season.
His only other ATP Tour match since then ended in defeat to Alexander Bublik in Monte Carlo last month.
