The world number one has reached the final at Flushing Meadows in each of the last four years, and is a strong favourite to make it five in a row in 2014.
And Djokovic rarely looked overly troubled against number 22 seed Kohlschreiber at Louis Armstrong Stadium as he advanced into the last eight of the tournament - where he will face Andy Murray or Jo-Wilfried Tsonga - with ease.
Kohlschreiber, who has never been beyond the fourth round in New York, had overcome home favourite John Isner in his previous outing, but he was unable to live with the seven-time grand-slam champion.
Djokovic - who has lost four of his five US Open finals, with his sole success coming in 2011 - made a flying start and raced into a 5-0 lead thanks to breaks in games two and four.
Although Kohlschreiber did get on the board in game six, Djokovic took the first set when he forced his opponent into a forehand error.
The second set was a much more closely fought affair, and it continued on serve until game 11, when Kohlschreiber undid all his good work by handing Djokovic a break with an unforced mistake on the forehand side.
Djokovic took full advantage to consolidate the break and seal the second set when the German sent a backhand into the net.
The Serb continued his momentum into the opening of the third, immediately breaking Kohlschreiber's serve in the very first game.
Kohlschreiber fought hard, but was unable to force any break points against Djokovic, who clinched his place in the quarter-finals when the German sent a backhand into the net.