Rather than giving up the point and settling for 15-15, Anderson scrambled to his feet, picking up his racket with his left hand and sending back a forehand return.
Playing Isner who is enshrined in Wimbledon folklore for winning the "endless match" - an 11 hour five minute humdinger against Frenchman Nicolas Mahut in 2010 - was never going to be easy for Anderson. That was played over on Court 18, which now bears a plaque commemorating the record-setter.
After beating eight-time champion Roger Federer, also over five sets in the quarter-finals, 2017 US Open runner-up Anderson claimed his 300th career win.
John Isner of the US leaves the court after being defeated by Kevin Anderson of South Africa in the men's semifinal match at Wimbledon on Friday.
Should Nadal prevail in the duo's record 52nd showdown, the Spaniard will play Anderson in a repeat of last year's US Open final in NY. There could be a rematch now.
Novak Djokovic led Rafael Nadal by two sets to one in their Wimbledon semi-final when it was halted for the night on Friday. And now he's lost the second-longest one ever played at the All England Club. The games between Isner and Anderson ticked by with a comforting, metronomic regularity over the first three or four sets.
The US Open is the only grand slam to use tiebreakers in the fifth set, with the Australian Open and French Open, like Wimbledon, both playing advantage sets. In that one was at Wimbledon too but came at a much earlier stage.
John Isner and Kevin Anderson simply refused to lose.
Williams vs Kerber in #Wimbledon ladies' final
She got past Germany's Görges without really breaking sweat and has enough energy to take on the next German in line. Moments later, Serena's misery was complete as a tame return left Kerber wiping away tears of joy.
The two big men - Anderson checks in at 6-foot-8, while Isner is 6-10 - traded blazing serves throughout the contest. Both wore a white baseball hat, Anderson with the brim in front, Isner with his turned his backward. Isner did not have his serve broken once in the tournament entering the match.
But this one was as competitive and close as can be. People watching at home would feel so riveted they would not dare leave it, nor ever forget it. Isner pounded his at up to 142 miles per hour; Anderson reached 136 miles per hour.
Many would argue Anderson and Isner deserve similar recognition after the great mates warmly embraced at the net before receiving a standing ovation from tennis's most famous centre-court crowd.
Tactically, there isn't much to describe it: both were nearly at the same level of serve and return, but for the break chances. Isner failed to convert a set point in the opener. Nadal took the second set and but was reeling behind in the third 3-1.
But the struggle to hold serve continued into the next game with Nadal immediately regaining his break advantage with a wonderful forehand victor.
Could he actually come through?
Who could blame him for needing a breather? Isner finished with 53 aces to Anderson's 49, and Isner during the fifth set broke the single-tournament aces record with his 214th.
Soon, they were meeting for an embrace.