Serbia's world No 1 defeated Kohlschreiber 6-1 7-5 6-4 on another muggy day at Flushing Meadows, reaching the last eight at the US Open for the eighth straight year.
It's his 22nd successive Grand Slam quarter-final, a run that stretches back to Kohlschreiber's victory over him in the third round of the 2009 French Open.
The Wimbledon champion looked headed for a short day's work when he raced through the first set in 25 minutes.
But Kohlschreiber dug in, keeping his nose in front on serve and forcing Djokovic to fend off a set point in the 10th game of the second.
Djokovic did so with a stinging forehand passing shot to end a rally that sent the Louis Armstrong Stadium crowd wild, then broke Kohlschreiber for a 6-5 lead.
Serving for the set Djokovic saved another break point with an off-speed service winner and having wrapped up the second set he broke Kohlschreiber to open the third and marched home from there.
Djokovic will play either eighth-seeded Andy Murray or ninth-seeded Jo-Wilfried Tsonga for a semi-final berth. Murray and Tsonga renewed an old rivalry in which the Scot has won nine of their 11 career meetings.
Tsonga, however, won their last encounter, beating Murray on the hardcourts of Toronto en route to the Masters title there in August.
Tsonga, who has reached the fourth round at all four Grand Slams this season for the first time in his career, arrived in New York on a high having also defeated Djokovic and 17-time Grand Slam champion Roger Federer in Toronto.
He remained wary, however, even though the 2012 US Open winner hasn't won a title since his historic Wimbledon triumph in 2013.
"It's never a good time to play Andy," Tsonga said. "For me, it's the best time to play against him just because I'm feeling better than a few months ago (but) to play against him it's never the good time."
Australian Open champion Stan Wawrinka, the third seed, takes on 16th-seeded Spaniard Tommy Robredo. Wawrinka beat Robredo in straight sets in the fourth round of the Australian Open en route to a breakthrough Grand Slam title in January.
That triumph was followed by a crushing first-round defeat at the French Open, and a quarter-final run at Wimbledon.
Two of the ATP's rising stars will duel under the floodlights as 23-year-old Canadian Milos Raonic and 24-year-old Kei Nishikori of Japan reprise their fourth-round clash at Wimbledon -- won by Raonic on his way to a first Grand Slam semi-final.
The fifth-seeded Raonic is enjoying a career-best season, and at a career-best number six in the world is the second-youngest player, behind 23-year-old Grigor Dimitrov, in the top 10.
Nishikori, the 10th seed, became the first Japanese man to break into the top 10 this season with two titles.
While Raonic has the reputation of a big-server -- with the second-most aces this year on the ATP tour, Nishikori has been impressive on his serve in reaching the last 16. He's been broken only twice, saving 17 of 19 break points he faced in his first three matches.