When Djokovic converted his second set point in the tiebreaker - having saved three of Nadal's - the clock had ticked a couple of minutes past 11.
With nobody budging on serve, a tie-break was needed to separate the pair and after some lung-busting rallies of epic proportions it was Djokovic who survived two set points before taking his own opportunity for the overnight advantage in a gripping contest. Still, Isner did jokingly ask chair umpire Marija Cicak at one point during the last set whether they could play a tiebreaker.
Isner hasn't been broken in 95 service games and has fired 161 aces, fuelled by a sweet tooth.
At least Anderson can boast of one runner-up finish, and it was recent, against Nadal at last year's U.S. Open.
"We always played in important stages, important places", said Nadal, who had a far rougher go of things in the quarterfinals than Djokovic, needing more than 4½ hours to edge Juan Martin del Potro in a five-set thriller.
Isner had nothing left to give, and his wait for a first Grand Slam final appearance will not come until at least the 42nd attempt, which is the record begrudgingly held by David Ferrer.
When Anderson finally broke Isner, he halted the American's streak of 110 consecutive holds at Wimbledon.
"So, I apologise if I'm not more excited right now.so many mixed emotions in getting through something like that". Djokovic retired in that match because of a toe blister.
He played well in the latter two sets of his four-set triumph over Kei Nishikori - a match that lasted "just" 158 minutes - and created 14 break point chances in 17 return games.
However, I am utterly shocked that the markets are finding it hard to split Nadal and today's opponent, Novak Djokovic, for the second semi-final, which will commence no earlier than 1500 United Kingdom time. "I'm a different person, different player today", Djokovic said.
The 31-year-old is eyeing a 13th major after making the semi-finals of a Slam for the first time since finishing runner-up at the 2016 US Open.
While Isner's match back in 2010 was a fun side note that helped garner interest in the tournament for fans it might not usually reach, to have a never-ending saga played in the semifinal doesn't look great for the sport.
Isner, 33, stands 6ft 10in and come the final points he looked nearly too tired to move for the ball. For us to be out there for that amount of time, I really hope we can address this.
"The effort they both put in and the performance and the guts, the way they competed - a lot to be proud of", said Justin Gimelstob, one of Isner's coaches.