The final set lasted for nearly three hours and delayed the second semi-final between Rafa Nadal and Novak Djokovic for so long that they were unable to complete their match.
With women's singles finalists Serena Williams and Angelique Kerber waiting in the locker room, Djokovic and Nadal hogged the stage as they continued where they left off the night before under the Centre Court roof.
Anderson, who had dethroned eight-time champion Roger Federer in the quarterfinals in a five-set thriller, advanced to his second grand slam finals.
Six hours and 36 minutes later South African Anderson had beaten an exhausted Isner 7-6 (8/6) 6-7 (5-7) 6-7 (9/11) 6-4 26-24.
His two-day semi-final victory over Rafael Nadal proved he was back to his best and he fought off a comeback from Anderson to win 6-2 6-2 7-6 (7/3), earning him a 13th grand slam trophy.
Paulina Dedaj is a writer/ reporter for Fox News.
"I think I did a great work".
"I feel pretty bad", Isner said in a news conference. If I was on the opposite side I don't know how you can take that playing for so long and coming out short... getting through something like that is quite different. He played the US Open finals previous year.
Kevin Anderson and John Isner made history in their astonishing Wimbledon semi-final on Friday. Anderson served for the third at 5-3, got broken, then had a pair of set points in that tiebreaker, double-faulting one away.
Anderson hit 49 aces and 118 winners in the epic contest on Centre Court.
"You know, a few days' rest, maybe more than that, and I'll recoup an Isner said that being part of yet another record-breaking match did not help ease his pain". The three-time champion led the match two sets to one.
Anderson triumphed 7-6 (8/6), 6-7 (5/7), 6-7 (9/11), 6-4, 26-24 in the second longest Grand Slam match ever played.
Isner and Anderson both had moments where they seemed to be slipping toward losing the break before having two big serves to swing it right back in their favor.
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.
Although both players had shown an ability to make inroads on their opponent's serve, the fifth set turned into a marathon featuring one service hold after another. I don't think he has much to lose.
"It's a bit of a sign for the grand slams to change this five-set format", he said. That's still a ton of serving, and it will be interesting to see what level of health and energy Anderson brings to the final. Another set point came at 9-8, but this time on Isner's serve, who saved it with a 138 mile-per-hour serve.
It was also the second longest match at a Slam, beating the six hours and 33 minutes which Fabrice Santoro spent seeing off Arnaud Clement in the 2004 French Open.
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