After a marathon five-set match, he won 7-6 6-7 6-7 6-4 26-24. After more than a year of trouble, Djokovic finally had surgery in February, then took a while to find his groove.
The ridiculous length of the Anderson-Isner clash left Nadal and Djokovic waiting until 8pm local time before stepping on court for their box office semi-final. The Spaniard fought off two break points to win the set in the ninth game.
"That definitely brings a smile to my face", said Anderson, the runner-up to Nadal at last year's U.S. Open.
"I'm a proponent of changing that rule, for sure. I'm sort of more focused on that than getting too excited about the overall picture".
When asked how he would recover from such an epic and play in the Wimbledon finals on Sunday afternoon, the South African said: "It's tough, I really don't know".
In the fifth set, Anderson broke Isner's serve at 24-24 to take command.
World number 10 Isner is best known to many fans, particularly in Great Britain, for his astonishing contest with Nicolas Mahut on Court 18 at Wimbledon in 2010. "I think I can keep doing damage here".
This was a match with two of the biggest servers in the game and neither disappointed in the aces department with 102 served, 49 by Anderson and 53 by the American eighth seed.
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This is not inevitable for me, I had a really tough delivery and multiple surgeries and nearly didn't make it to be honest. Told that Kensington Palace had announced the Duchess would be there, Serena smiled and said: "There you go".
Play was halted Friday after 2 hours, 54 minutes, with Djokovic leading two sets to one, 6-4, 3-6, 7-6 (9).
It was the kind of ingeniousness that was needed to break the serve-hold-serve-hold deadlock that went on for nearly three hours in the deciding set alone as Anderson became the first South African man in 97 years to reach the Wimbledon final.
The crowd knew it, the spectators knew and although Isner might not be willing to admit it, Anderson did. At the 11th hour, literally and figuratively, Djokovic grabbed his first set point, but hit long for 9-all, then got a second look as a Nadal drop-shot sat up invitingly for him. Djokovic was in the lead two-sets to one when play was halted. Anderson, who typically shows a reserved demeanor, would frequently fist-pump after winning a point. He has reached a career-high in the rankings and on Wednesday he defeated Canadian Milos Raonic in the Wimbledon quarterfinals, advancing the furthest he ever has in a Grand Slam tournament.
"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 mishit a backhand.
He had break points in the 15th, 21st and 35th games of the decider before taking victory when a tired Isner, who had needed treatment for blisters on his right hand, hit long.
And repeatedly, the answer was, of course, "No", even when Anderson smacked a return victor at Isner's feet to get to break point at 7-all, 30-40.
In the 50th game, Isner took down the opening point before Anderson captured the next four - including two on aces.