He reached the final of the US Open past year before losing to Rafael Nadal.
On Friday in the semifinals, Anderson won the first set 7-6 (6) in 63 minutes.
Anderson had a break and set point chance at 5-4, but Isner fired down a gutsy 129mph unreturned second serve to keep himself in contention.
Again, the pair traded breaks early in the fourth, but Anderson broke and eventually served it out to take the match into a decider after three hours and 40 minutes.
A showdown between two tennis skyscrapers - with Isner topping the 6 foot 8 Anderson by two inches - predictably featured three tiebreaks and 102 thunderbolt aces but it was the 32-year-old South African who delivered the knockout blow. The two went back and forth all the way to 12-all, essentially playing a full sixth and seventh set.
The fifth set got off to a quick start but then turned into a marathon.
As it became clear that Isner was due for another endless fifth set, tennis fans were far from delighted.
GLOW gets Emmy nomination love, no luck for WWE
"Maisel", Amazon Studios' popular series set in a very Jewish 1950s NY neighborhood, was nominated for best comedy series. ABC's Black-ish has managed to increase its Emmy nomination tally a little bit every year of its existence.
There was some fear that the match would be stopped when rain began to fall in the fifth, and the grounds crew sprung into position, but play continued.
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.
Anderson had beaten 20-time Grand Slam champion Roger Federer to reach the semifinal against Isner. He beat the defending champion 2-6, 6-7, 7-5, 6-4, 13-11 in a match that lasted over four hours.
Anderson said he had "mixed emotions" after the epic match.
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.
But Anderson has little time to rest his aching body before facing Novak Djokovic or Rafael Nadal in Sunday's final.