The 6-foot-10 (208 cm) Isner finally succumbed to the 6-foot-8 (203 cm) Anderson just before 8 p.m. local time Friday in a grueling encounter full of plot twists in the longest men's semifinal in grand slam history and the third longest match of all time. It started at 1 p.m. local time.
The fifth set alone involved 50 games with Anderson eventually triumphing 7-6 (8-6) 6-7 (5-7) 6-7 (9-11) 6-4 26-24 in what was also the longest single-day match ever at the grass court tournament.
The result came two days after Anderson stunned eight-time champion Roger Federer in four hours and five more sets, saving a match point in the process.
"I don't really know what to say right now," Anderson told the BBC.
"It was really tough for both of us. Somebody has to win, John is such a great guy and I really feel for him," added Anderson, who has known Isner for 14 years after their time playing college tennis in the US.
Anderson will face a giant of a different kind in the men's final Sunday -- either twice champion Rafael Nadal of Spain or three-time winner Novak Djokovic, who posted a picture on social media of himself playing marbles while waiting for Isner and Anderson to finish.
The pair faced off for a men's record 52nd time in their careers in the other semifinal, which Djokovic led 6-4 3-6 7-6 (13-11) when play was suspended at 11:03 p.m.
Although the All England Club has a retractable roof with lights, a curfew of 11 p.m. is implemented in order not to disturb its residential neighbors in southwest London. The match will resume Saturday ahead of the women's final between Serena Williams and Angelique Kerber.
Serbia's Djokovic had beaten the current world No. 1 in the 2011 final, the last time Nadal advanced beyond the fourth round until this year. And he held the upper hand Friday after saving three set points in the gripping tiebreak.
But if Nadal rallies, he would encounter Anderson in a second grand slam final in less than a year, having toppled the 32-year-old at the US Open last September.
In 2010, Isner famously won the longest tennis match of all time, beating France's Nicolas Mahut 70-68 in the final set in a contest that lasted 11 hours, 5 minutes, took three days to complete and featured 216 aces.
But his record in fifth sets slumped to 9-18 overall, including defeats of 19-17, 18-16, 12-10 and now 26-24.
"I feel pretty terrible," Isner said in a news conference. "My left heel is killing me. I have an awful blister on my right foot."
The match time beat the previous Wimbledon semifinal record of four hours, 44 minutes set by Djokovic and Juan Martin del Potro in 2013.
When asked how he would recover and play in the final Sunday, Anderson said: "It's tough, I really don't know."
The final set of a men's singles match at Wimbledon is traditionally decided by a difference of two games, like at the Australian Open and French Open. The US Open is the lone major that has a tiebreak in the deciding set.
Anderson called for change.
"It's a bit of a sign for the grand slams to change this five-set format," he said.
Isner, who lost his second-round match in 2010 because he could barely move after beating Mahut, agreed.
"if one person can't finish the other off before 12-all, then do a tiebreaker there," Isner said. "I think it's long overdue."
The match between Isner and Anderson -- the first South African male to reach the Wimbledon final since Brian Norton in 1921 -- featured 102 aces, with only 22 rallies going to nine points or more.
Isner, who previously said Wimbledon had become "a house of horrors" for him since his 2010 match, had been trying to become the first American man to reach the final since Andy Roddick in 2009.
Having served 284 aces between them to reach their first Wimbledon semifinal and first and second in aces on tour this year, not many service breaks were expected in the 12th duel between Anderson and Isner.
After Isner saved a set point at 5-4 in the first with a 129 mile-per-hour second serve into the body, the match went, predictably, to a tiebreak. At 6-5, Anderson saved a set point with a smash on his serve and went on to take the opener 7-6 (10-8) in 63 minutes on two errors by his opponent.
Anderson dropped the second set on a tiebreak despite making only one unforced error before a see-saw third full of momentum changes followed, with both men creating chances but unable to take them.
After two-and-a-half hours of play, Anderson managed to clinch the first break of serve in the match to end a run of 110 straight service games held by the 33-year-old at Wimbledon this fortnight.
Remarkably, Isner broke straight back as Anderson failed to serve it out from 5-3, 30-15.
After saving two set points in the third set tiebreak, Anderson blew his first set point at 8-7 with a double fault. Another set point came at 9-8, but this time on Isner's serve, who saved it with a 138 mile-per-hour serve. The American roared and turned to his box as he took the third set on his third set point.
Having once again swapped breaks early on in the fourth set, Anderson broke Isner for the third time, and took the match into a decider on his fourth set point.
"We don't want it to be 70-68, John," someone shouted from the crowd at 8-8.
Anderson had a break point at 7-7 and at 10-10, but he missed the first one as Isner hit an ace and the second one as he erred on a backhand passing shot.
Then, 122 minutes into the fifth set, the crowd went wild as a tired-looking Isner faced two more break points, only to save them with back-to-back aces as dark rain clouds gathered over Centre Court.
With Isner serving at 24-24, 0-15, the right-handed Anderson fell down, dropped his racket, got up and played the point left-handed. After 170 minutes into the fifth set, he finally broke Isner's serve as the American made a backhand error.
Meanwhile, Anderson didn't face a break point in the fifth set.
With Anderson serving for the final at 25-24, Isner handed his opponent two match points when a return sailed long. Anderson moved to his first Wimbledon final as Isner produced his 59th unforced error.