Murray won the first of his three career majors at the U.S. Open in 2012 and will be the favourite to make a fourth semifinal at the season’s last Grand Slam.
The world number two has a 7-1 record against Nishikori whose only win over the Briton came at the World Tour Finals in 2014.
This year, Murray came out on top in five sets to help steer Britain past Japan in the Davis Cup before cantering to a straight sets win in the Olympics semifinals.
All in all, Murray is on a 26-1 run since losing the French Open final to Djokovic in June, collecting the Queen’s Club, Wimbledon and Olympic titles on the way.
But he won’t underestimate the threat posed by Nishikori, who made the final in New York in 2014 having knocked out Djokovic in the semifinals.
“He played some good stuff at the Olympics and won the bronze,” said Murray who reached the quarterfinal with a brutal dismissal of Grigor Dimitrov where he lost just five games.
“I played a really good match against Kei in Rio and I’ll need to do that again if I want to beat him because he’s one of the best players in the world, plays extremely well on hard court.”
Djokovic targets a 10th successive semi-final appearance on Tuesday when he faces longtime rival Jo-Wilfried Tsonga, one of three Frenchmen in the last-eight.
World number one Djokovic, the champion in New York in 2011 and 2015, has hardly broken sweat in the first four rounds.
He needed four sets to beat Jerzy Janowicz in his first match before he enjoyed a walkover in the second, an injury-enforced retirement in the third followed by a comfortable win over Briton’s Kyle Edmund in the last-16.
In Tuesday’s other men’s quarter-final, Lucas Pouille, who knocked out 14-time major winner Rafael Nadal in five sets on Sunday, faces French compatriot Gael Monfils.
Triple French threat
It is the first time since 1927 that three Frenchmen have reached the last-eight in New York.
Djokovic, looking for his third major of 2016, boasts a remarkable record in New York.
As well as his two titles, the 29-year-old was runner-up in 2007, 2010, 2012 and 2013. He was a semi-finalist in 2005, 2006 and 2014.
The Serb has a 15-6 winning record against ninth seed Tsonga, a run stretching back to their first meeting in the 2008 Australian Open final.
“I’m feeling very good. I didn’t have much time on the court overall before the fourth round,” said Djokovic who came into the tournament suffering from a wrist injury.
“Considering I had some struggles before the tournament, I feel great at this moment physically; mentally as well I’m motivated.”
Monfils beat Pouille in their only meeting — in five sets in the first round of the Australian Open in 2015.
But 22-year-old Pouille is now Grand Slam hardened having made a maiden Slam quarter-final at Wimbledon.
Monfils, who turned 30 on September 1, is in his third quarter-final in New York. In his last appearance at this stage in 2014, he squandered a two sets lead against Roger Federer.
Wedneday’s other quarter-final sees 2009 champion Juan Martin del Potro, ranked at 142 but on the comeback trail after three wrist surgeries, tackle third seed Stan Wawrinka, a former Australian and French Open winner.
Del Potro, the lowest-ranked quarter-finalist in 25 years, has a 4-2 head-to-head record over the 31-year-old Swiss including an impressive victory at Wimbledon earlier this year.
However, the two have never met on hard courts.
The quarterfinal has been dubbed as a battle between Del Potro’s hammer of a forehand and Wawrinka’s precision backhand.
“It’s going to be good challenge to play against him,” said Wawrinka who is in his fourth successive US Open quarter-final and is a two-time semi-finalist.
“It’s going to be important to try to dictate and be aggressive on the court.”