But no-one worked harder, or longer, for their victory than Japan's Kei Nishikori, who needed five sets and four hours and 19 minutes to tame fifth seeded Canadian Milos Raonic 4-6 7-6 (4) 6-7 (6) 7-5 6-4.
The marathon contest equalled the latest finishing match ever played at the U.S. Open with the two exhausted players walking off the Arthur Ashe Stadium court at 02:26 AM local time - exactly equalling the record for the latest-ever finish at Flushing Meadows.
Andy Murray also made it through, outclassing Jo-Wilfried Tsonga to earn a last-eight match against Djokovic.
[FULL REPORT: Murray outclasses Tsonga to set up Djokovic showdown ]
Djokovic, who has reached the final at Flushing Meadows each of the last four years and won it all in 2011, has been in storming form, giving every indication that the big Serb plans to be playing for the title again on September 8.
It marks the 22nd consecutive grand slam that Djokovic has advanced at least to the quarter-finals and eighth straight at the US Open.
"I'm very glad obviously that I had so many consecutive quarter-finals of grand slams, it says that I do value these tournaments the most and try to always perform my best tennis in them," said Djokovic, will now take on eighth seeded Scotsman Murray, who fended off ninth seeded Frenchman Tsonga 7-5 7-5 6-4 in intense heat at Flushing Meadows.
"Obviously it motivates me for the future to continue that streak, of course," he added.
The last time Djokovic failed to reach the last eight at a major Kohlschreiber blocked his way with a third round victory at the 2009 French Open.
There was no danger of a repeat on Monday.
The top seed needed just 19 minutes to race in front 5-0 lead before the 22nd seeded Kohlschreiber finally held serve to halt the slide.
But the small victory could not stop the inevitable as Djokovic wrapped up the first set and then went on to claim the match in a touch over two hours without surrendering a break.
Djokovic has advanced to the last eight without dropping a set and a quick end to his fourth round clash was appreciated by all with on court temperatures hovering near 100 degrees Fahrenheit (38 Celsius).
"Obviously in the match you go through times where you feel better, where you feel worse, depending on your emotional state, depending on the level of performance of your opponent, how much pressure he puts on you and so forth," explained Djokovic. "It varies. You have ups and downs.
"It's important obviously in these particular conditions not to get carried away by, you know, frustration of heat. Especially after long rallies try to get extra breath.
"Everybody is different, but I tried to focus on each point individually, because I know that I definitely wanted to stay not too long there...I wanted to get the job done in three."
Djokovic, who had won only two matches in the hard court run-up to Flushing Meadows after getting married just days following his Wimbledon triumph, has looked like his old dominating self.
The Serb has been all business and declared himself fit, focused and ready to make a run at second U.S. Open title.
"As we come closer and closer to the finish line the matches will get tougher, so that's where I will see where my game is and if I'm mentally strong enough to hold on," said Djokovic. "I have had a great Wimbledon run; Roland Garros, great clay court season. So I want to continue on.
"I want to build on that.
"I feel good about my game, myself. My physical state is pretty good. I'm fit. This is something that is obviously encouraging me for the next one."
Australian Open champion Stan Wawrinka fought off two set points in the pivotal third set on the way to a 7-5 4-6 7-6(7) 6-2 win over Spain's Tommy Robredo to earn a quarter-final against Nishikori.
After splitting the first two sets, the third-seeded Swiss trailed 6-4 in the third-set tiebreaker but battled back to win 9-7 and closed out the victory over the Spanish 16th seed in the fourth set.
"It was a really tough battle today. It's always tough to play against him, he is always fighting," said Wawrinka, who showed his competitive fire with a dive into the stands during a point in the tight confines of Louis Armstrong Stadium.
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