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.
The 32-year-old Anderson triumphed 7-6 (8/6), 6-7 (5/7), 6-7 (9/11), 6-4, 26-24 after six hours and 36 minutes on Centre Court.
Despite going on for almost seven hours, Isner was nowhere close to beating his own record for the longest tennis match history - a first-round victory over Nicolas Mahut, which went on for more than 11 hours over three days and finished 70-68 in the fifth in 2010 also at Wimbledon.
Anderson, who had dethroned eight-time champion Roger Federer in the quarterfinals in a five-set thriller, advanced to his second grand slam finals.
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"Playing like that in those conditions is tough on both of us", Anderson said afterwards.
John Isner is 8-3 in his career against Kevin Anderson. Hopefully they appreciated the battle that we faced out there against each other, but if you ask majority, I'm sure they would have preferred to see a fifth-set tie-breaker, too.
"My results were not up to the standard that I had before", said Djokovic after beating Kei Nishikori in the quarter-finals. After losing the second set, he turned into Vintage Djoker and won 12 of the next 16 games to return to the Wimbledon semis for the seventh time.
"I really hope we can look at this and address this because in the end you don't even feel that great out there", the eighth seed said.
The two have played some memorable matches over the years.
Remarkably Djokovic holds the slimmest of advantages at 26-25. "I think it's long overdue".
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Anderson had nearly surely forced the game back to deuce with a close-range dink over the net, but a exhausted Isner somehow stormed across the court to slam home a passing victor.
Both players held serve all the way through the third set and into the tiebreaker, which saw Nadal fail to convert three separate set-point opportunities, including one on his own serve.
Anderson weighed in with 49 aces to reach 172 so far.
After 6ft 8in Anderson edged the opening tie-break he eked out another break point in the second set, but once again Isner repelled it and this time the tie-break went the way of the American.
World number one Nadal, the 2008 and 2010 champion at the All England Club, trails Djokovic, the 2011, 2014 and 2015 victor, 26-25 in a rivalry which began at Roland Garros 12 years ago.
Isner hadn't been broken in London throughout his run to his first Grand Slam championship semifinal. The most important came with Isner serving at 24-24.
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NADAL-DJOKOVIC DELAYED That recovery process started as soon as he came off Centre Court at 7:46 p.m. on Friday.