Roger Federer is also into the quarters in his for a 100th title.
Cilic, who will make the cut for London if he downs Djokovic, ended reigning ATP Finals champion Dimitrov's season.
Over the last seven or eight years, we had some great runs from all the players from the "Big 4" but there was never a chance to see three of them at the top of the standings in a single year until now, achieving that at the combined age of 99 in another testimony of their everlasting supremacy!
Third seed Federer is playing the Paris Masters for the first time since 2015 and is bidding to clinch the tournament for just the second time after winning it in 2011.
Djokovic reached the last 16 in Paris by defeating Joao Sousa on Tuesday, his 19th consecutive win on the ATP World Tour.
Nishikori beat Frenchman Adrian Mannarino 7-5, 6-4 while Isner battled past Mikhail Kukushkin 6-3, 6-7 (2), 7-6 (1).
Yet his opponent, Milos Raonic, pulled out because of injury, leaving Federer to think that it had actually turned out to be a blessing in disguise.
Federer also revealed he had received an invite to take part in an exhibition featuring Nadal and Djokovic in Saudi Arabia in December, but the 37-year-old said he turned down the approach.
Isner's United States compatriot Jack Sock, who's the defending Paris Masters champion, also advanced with a 6-0 6-4 triumph over Malek Jaziri. "If he has a high first serve percentage, then it's obviously a big challenge to play him because he's got a really big game from back of the court".
Fourth-seeded Alexander Zverev saved all four break points he faced in beating Diego Schwartzman 6-4, 6-2.
Fifth-seeded Marin Cilic, the Australian Open runner-up, won his second-round match 6-3, 6-4 against Philipp Kohlschreiber of Germany. Round 3 may bring the ever-improving power player, Karen Khachanov, and this quarter is topped by Alexander Zverev, whose debut here previous year ended in the second round.
John Isner, however, is set to miss the Finals after losing to Karen Khachanov in a tussle featuring two tie-breaks in nearly two and a half hours.
Sock next faces No. 6 Dominic Thiem, who used 14 aces as he rallied to beat No. 11 Borna Coric 6-7 (3), 6-2, 7-5.