The Serbian recovered from losing the first set as he struck 45 winners to move past the 31-year-old 6-7(4) 6-3, 6-3, 6-2 in three hours and 32 minutes, improving to 18-2 in their ATP Head2Head Series.
Djokovic, who can also pass Roger Federer and Rafael Nadal for most Slam titles with his 21st major trophy in New York, is now just four victories away from becoming the second man in the Open Era alongside Rod Laver in 1969 to capture the Grand Slam, having triumphed at the first three majors of the season.
The World No. 1 has claimed 17 consecutive victories against Nishikori, last falling to the 31-year-old in the semi-finals at the US Open in 2014. The 85-time tour-level titlist recently defeated Nishikori at the Tokyo Olympics, dropping just two games en route to his victory.
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In a lively start, Nishikori caused problems for the top seed in the first set as he fired the ball with consistent power and depth to force Djokovic into uncharacteristic unforced errors, with the Serbian committing 20 in the set. While Djokovic did break back as they moved to a tie-break, Nishikori then held his nerve to lead when Djokovic hit a forehand return long.
The Serbian changed the shape of the match in the second set though, raising his intensity as he cut down on mistakes and started to find the corners with his groundstrokes, manoeuvring Nishikori around the court as he broke twice to level. Djokovic continued to pin the 31-year-old behind the baseline with his flat backhand in the third set and recovered from dropping his serve at 4-2 to move ahead. The World No. 1 then fired 10 winners, hitting four aces in the fourth set to advance.
Nishikori was making his 12th appearance at the US Open and was aiming to reach his fourth quarter-final in New York. The World No. 56 enjoyed a run to the semi-final in Washington, while also reaching the last eight on hard in Dubai and Rotterdam earlier this year.
“Well, [it was a] tough loss,” Nishikori said in his post-match press conference. “I thought I was playing much better than the last couple matches we played [but] in some moments he was playing very solid that I couldn’t, like, break the wall.”