Djokovic had four break points in the first two service games alone and suffered a Wimbledon meltdown as he bounced his racket off the ground, argued with the umpire, and then went on to lose the second set.
It is Djokovic's first appearance in the semi-finals at the All England Club since 2015 - when he last won the title - and he revealed his motivation is fully back as he chases Grand Slam title No. 13.
He continued to set high standards for the remainder of the set, and despite flurries from Djokovic, Nishikori made the most of his advantage and levelled the match.
The match was played there after Novak Djokovic, having played three of his opening four matches away from Centre Court, had his request to play in the main stadium granted.
After seeing off big servers Kyle Edmund and Karen Khachanov, he faced Nishikori, who had recovered from his own serious injury to hit peak form in reaching his first Wimbledon quarter-final.
Japan's Kei Nishikori bowed out of Wimbledon on Wednesday after losing to Novak Djokovic of Serbia 6-3, 3-6, 6-2, 6-2 in the quarter finals of the grass-court major.
Fifth seed Juan Martin del Potro met stubborn resistance from Frenchman Gilles Simon and had to settle for a suspension of their Wimbledon fourth round match as he led 7-6 (1) 7-6 (5) 5-7 after more than three hours on Court Two on Monday.
"I thought it was unnecessary to get the warning", he told the BBC after the 6-3 3-6 6-2 6-2 win. I didn't harm the grass. "In the midst of emotions in a tough match, it happens".
Djokovic, three times a champion at SW19, maintained the dominance he has shown throughout the tournament on his first serve.
Nishikori, who had won only two matches in 15 meetings with the 12-time major victor, broke for 1-0 in the fourth but was broken straight back. "I knew how I threw the racket", Djokovic later explained.
"Double standards, my friend".
After the match, Djokovic admitted his frustration at Ramos's decision, while pointing out that Nishikori did exactly the same thing in the fourth set.
But the 12-times major victor regained his cool sufficiently enough to safely take his place in the semi-finals for the first time since snaring his third title at The All England Club in 2015.
Tory vice chairs quit over Brexit
He has also said he might speak to Boris Johnson , who quit as foreign secretary over May's plans. Dominic Raab was appointed Brexit secretary by Mrs May after Davis' resignation .