This was Nadal and Djokovic's 52nd meeting - more than any other two men in the Open era - and the pair did not disappoint as they finally resumed their long-standing rivalry on the Grand Slam stage.
The other semifinal match will still take place Friday, but the curfew for play at Wimbledon is 11 p.m. local time.
Isner then shrugged off needing treatment on a blistered serving hand, found time to usher a ladybird to safety before levelling the match in another tiebreak off his 19th ace.
Nadal disagreed with the decision to keep the Centre Court roof closed as he lost an epic clash to old rival Djokovic on Saturday.
In the second longest match in Wimbledon history, Anderson triumphed after 6 hours and 36 minutes, 7-6 (6) 6-7 (5) 6-7 (9) 6-4 26-24. There is no set time for the match to end, and they can often go on for more than two hours.
Nadal faced a break point at 4-3 behind but roared away from trouble with a powerful first serve followed by two vicious, whipped forehand winners.
It's the first time in almost a century that a South African's made it to the end of the competition, and no South African has ever won the tournament.
He also improved to third all-time with his 13th career victory against a player ranked No. 1 since the world rankings were introduced in 1973.
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Serena Williams , a close friend and wedding guest of the Duchess of Sussex , will be facing Germany's Angelique Kerber . Ms Williams continued: "We have always supported each other, just been there for each other through a lot".
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It is understood that more than 20 supporters were identified by the authorities and they lost their FAN-IDs and were sent home. There have also been multiple cases of female reporters being groped and kissed by male fans during live broadcasts.
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As revealed by SPORT , Barcelona spoke with Hazard's agent last week and they were told the player wants to leave Chelsea . Nevertheless, losing a player of his talent would be a devastating blow to the Blues and arriving manager, Maurizio Sarri.
There's no doubt Djokovic will be a big favourite, even if he did need to play almost 2 1/2 hours Saturday while Anderson was able to rest and relax and recover.
But I wouldn't necessarily say I've been playing like incredible.
"It is what it is", Djokovic told the BBC upon coming off court.
Nadal missed 5 break points in the decider and had to pay the price at last as 12-time Grand Slam champion Djokovic reached the major's final.
The two players are due to walk onto court at 2pm, meaning play will start at around 2.10pm after the coin toss and after once they have both warmed up.
If Wimbledon's 2018 men's championship is remembered for anything, it may be its role in bringing about fifth-set tiebreaks.
That has led to some extremely long fifth sets, particularly at Wimbledon, where the grass court accentuates the punch of the serve and makes it more hard to break serve.
Isner was (and maybe still is) best known for 2010 Wimbledon, when he beat Frenchman Nicolas Mahut 70-68 in the fifth set in the longest match in tennis history (11 hours, 5 minutes over three days).
It was one of three successful drop shots from the Spaniard in the tiebreaker alone, but Djokovic answered with one of his own to save the second set point at 7-6. Both he and Anderson have had solid serves, but Djokovic's defense against Nadal made all the difference.