Del Potro saved two break points in the sixth game, a deft chip from the baseline that dipped over the net followed by a forehand victor, before taking the opening set in a 7-1 tiebreak.
Failing to take advantage of three break points at 2-2, he lost his own serve to go 4-2 down in what came to be a turning point.
"I'm very grateful that I have the opportunity to play the sport that I love at this high level and I've worked very hard to get myself in the best possible shape for the biggest events". "I have been building over the last couple of weeks, and the level of tennis I have played in the last couple of months felt like it was getting better and better and I feel like I am peaking at the right moment".
"Obviously it's different coming into semi-finals this year, taking in consideration 15 months behind, what everything that has happened, my results that were not up to the standard that I was doing before, that I was expected to play on", he said. It's his first Grand Slam final four appearance since 2016, and his eighth career semifinal at the All England Club.
Novak Djokovic is in his first semifinals of a Grand Slam in just under two years, but is angry at just about everything. Despite his anger, Djokovic still reeled off 10 of the last 12 games of the quarter-final.
He dropped out of the world's top 20 in May - yet his performance in June at Queen's, where he reached the final, suggested the 31-year-old could reach the second week at Wimbledon.
Victory always appeared likely to be a tall order for Nishikori, who has lost to three-time Wimbledon champion Djokovic in 13 of 15 previous matches.
The Serb looked in impressive form, particularly when he closed out the final set in ruthless fashion to set up a blockbuster semi-final with world number one Rafa Nadal. But the Japanese showed great fight in the second set when he survived four break points and made it one set each for the quarter finalists. He was within touching distance as he held to 30 for a 5-2 buffer and, much like the preceding set, he rammed home his superiority to seal the set - and the match - with a double break.
The 24th-seeded Nishikori was able to attack Djokovic's second serve and had a chance to take the lead when he was 0-40 up at 2-2 in the third set.
Novak Djokovic was kept waiting in the wings till after 7 pm local time before he could start swinging his racket against Russia's Karen Khachanov at Wimbledon on Monday.
Djokovic, victor of three singles titles at the All England Club, will next meet Japan's 24th seed Kei Nishikori. "He was playing, you know, good tennis again", said the Japanese.