Only in this last 18 months has he been able to restore his glory, with successive French Open titles, and a US Open victory.
Nadal was knocked out in the fourth round, losing 13-11 in the final set to Luxembourg journeyman Gilles Muller.
"I was playing tennis". I was close to beating him and I couldn't. The victor will get a chance to play at the biggest stage in tennis.
In an odd-numbered year, the exit of Roger Federer in a five-set thriller, followed immediately by the triumph of Rafa Nadal in a five-set thriller on Centre Court, would have dominated the sports pages, but unfortunately for tennis fans, England had to go and get to and get beat to Croatia.
Their match-up has provided some of the most memorable moments in this sport - with their rivalry peaking in the 2012 Australian Open final.
"Always is a big challenge face Novak". It is always a big test. "You know you can't win against him if you don't play very well", he said.
Djokovic came into the Championships on the back of a frustrating year which was blighted by an elbow injury and saw him slide down the world rankings as a result. Except this was a quarter-final, so the stakes felt slightly lower. "I tried to resist and maintain focus".
"I play Los Cabos in Mexico - the beach", he smiled.
But the second seed stayed alive by taking the fourth set before the gripping drama continued in an electrifying deciding set in which both players were left diving after volleys and slipping over as they sprinted after blinding winners.
"Of course I was anxious when I lost the second set", said Nadal, who had reached the quarter-finals without dropping a set and might have continued that run had he not squandered four set points, including one with a double fault, in the tiebreak.
Isner's grass data over the last two years is also marginally better than Anderson's, so he does look to hold a slight edge in his quest to reach his first ever Grand Slam final.
A set littered with one lengthy rally after another, eventually went to Nadal on serve, finally giving him the match.
Isner and Anderson also share the distinction of each owning arguably the most feared serve in tennis, meaning long rallies will be nearly non-existent this afternoon.
While Nadal and Djokovic are old hands at winning Slams, the man stood on the opposite side of the net in Sunday's final will be bidding to win a first major.
At the other end of the spectrum, are 33-year-old Isner and 32-year-old Anderson who have scripted their best performance at Wimbledon by make the final-four.
Nadal, meanwhile, is appearing in his first Wimbledon semifinal since 2011.
"I said at the beginning of the tournament, getting through to the quarters was a big goal of mine", he said. So far the four matches have been really, really good for me'.
Head-to-head, Isner leads 8-3, but this is the first time they've met at a Grand Slam.
"But my goal is to try to play very well".
"I just kept saying "today is going to be your day".