Isner previously won the longest ever Grand Slam singles match against Nicolas Mahut, lasting 11 hours and five minutes over three days in the 2010 Wimbledon first round.
After winning the first set, Anderson then lost the following two sets, with the first three sets all needing a tie-breaker to separate the two men.
It is common to hear the call of 15-all in tennis, but, in this instance, that was the score in games at one stage in the fifth set as both players continued to resolutely hold serve. It was a drama filled set that went back-and-forth, similar to the third set.
On the most crucial point of the match, Anderson recovered after a fall and hit a lefty forehand to go up 0-30 while Isner was serving at 24-24.
With a spot in the Wimbledon final on the line, the two power players beat each other to a standstill in a match that stretched nearly seven hours.
The 99 total games made it the longest Grand Slam semifinal match in the Open Era, beating the previous mark of 90 set by Rod Laver and Tony Roche in the 1969 Australian Open. Some fans were shocked and awed by the sheer length and absurdity of the contest, while others also voiced a frustration with the first match of the day delaying the real headliner - the semifinal matchup between Rafael Nadal and Novak Djokovic.
And another all-time great awaits him on Sunday in either Nadal or Djokovic.