On Sunday night, Wawrinka broke for a 6-4, 7-5, 2-1 lead over the World No. 1 in the fourth round when the 16-time Grand Slam champion retired due to injury.
In a rematch of the 2016 US Open final, which was won by Wawrinka in four sets, the No. 23 seed defeated the Serb for the fifth time (5-21) and he is into the last eight at the season's final Grand Slam for the fifth time in his six most recent appearances.
Djokovic, who received treatment on his left shoulder after the second set, had not lost before the quarter-finals at the US Open since 2006, when he was only 19.
Wawrinka, 34, will now face Cincinnati champion Daniil Medvedev, who secured a 3-6, 6-3, 6-2, 7-6 victory over qualifier Dominik Koepfer to book his place in the quarter-finals.
Meanwhile, Swiss legend Roger Federer crushed David Goffin in only 79 minutes to reach the quarter-finals.
Federer advanced to the US Open quarter-finals for the 13th time in his past 15 attempts by defeating Belgian 15th seed Goffin 6-2, 6-2, 6-0.
The 38-year-old, trying to stretch his men's Grand Slam record title total to 21, will now lock horns with Bulgaria's 78th-ranked Grigor Dimitrov.
18-time Grand Slam winner Rafael Nadal, who has never faced Federer at the US Open, will also return to court on Monday seeking a last-eight berth on the other side of the draw against 2014 US Open champion Marin Cilic.
( With inputs from IANS )