The pair broke the record for SW19's longest ever semi-final match during the fifth set, surpassing the 2013 clash between Novak Djokovic and Juan Martin Del Potro, which lasted four hours and 43 minutes.
John Isner and Kevin Anderson have called for fifth set tie breaks at the Grand Slams after their marathon Wimbledon semi-final. I really feel for him, because if I had been on the opposite end of this, I don't know how you can take that playing for so long and coming up short.
"It just seems cruel and unusual punishment for these guys", former champion John McEnroe said on the BBC.
"I feel pretty bad", Isner said afterward. "I had surgery when I was quite young, and my dad, who coached me throughout my career, said, 'learn to play left-handed.' I didn't know that was going to come into play at this point in my career, at this stage, but that was obviously a vital point for me in the end". "I have an very bad blister on my right foot". They combined for 102 aces, 53 by Isner, 49 by Anderson.
It was a severe test of stamina for both players, as well as those watching, and meant a long wait for Rafael Nadal and Novak Djokovic who were due on next in the second semi-final.
Anderson, who had dethroned eight-time champion Roger Federer in the quarterfinals in a five-set thriller, advanced to his second grand slam finals.
Anderson does have experience of making it to the title match at a Major, having reached the US Open final last September (lost to Nadal).
Djokovic's 2017 Wimbledon campaign ended in a quarter-final retirement with an elbow injury which led to surgery and precipitated a worrying dip in form and confidence.
Isner said he agreed with Anderson that tiebreakers - at some point in the fifth set - were the way to go.
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The eighth-seeded Anderson became the first person to break the serve of ninth-seeded Isner, doing so once in the third set, twice in the fourth set and again during the fifth set.
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.
The 33-year-old agreed with Anderson that Wimbledon, the Australian Open and Roland Garros should fall in line with the US Open and introduce a tiebreak in the final set.
Williams defeated Kerber with a 7-5 6-3 victory over the German at Wimbledon two years ago.
Isner said that being part of yet another record-breaking match did not help ease his pain.
Anderson began his Wimbledon with a 6-3 6-4 6-4 victory over qualifier Norbert Gombos before beating Andreas Seppi 6-3 6-7 6-3 6-4.
With Djokovic hitting the lines with relentless regularity, Nadal saved two more break points at 1-1 then seized the initiative to punish Djokovic for his first lapse.
Nadal and Djokovic were meeting for the 52nd time.
Djokovic retired in that match because of a toe blister. Of the four Grand Slam events, only the U.S. Open uses a final-set tiebreaker.