"I just patiently waited for the moment and it happened".
A confident Tsitsipas sent a blistering forehand to the back corner while the ninth-seeded Serbian was heading the other way on his first match point to secure the win before looking at his box in disbelief.
Djokovic, the victor of 30 career Masters titles. will next face either seventh seed Dominic Thiem, who has yet to step on to a hard court this summer with the US Open just over a fortnight away, or rising Greek youngster Stefanos Tsitsipas.
Tsitsipas upset Novak Djokovic 6-3, 6-7 (5), 6-3 in third-round play at the Rogers Cup in a thrilling battle between one of the Tour's top young guns and the reigning Wimbledon champion.
"I actually feel like there is more time now than before because the shot clock starts counting down once the chair umpire calls the score", Djokovic said.
Djokovic, a four-time Rogers Cup champion, faded late on a warm, breezy afternoon at Aviva Centre on the York University campus.
"Sorry to my fans in Toronto, but I have to pull out of the tournament since my left wrist needs some days of rest", Del Potro said in a tweet.
In the third set, the teenager showed great composure to break for a 2-0 lead and then saved a break point for a 3-0 margin.
Tsitsipas set up match point with a scorching crosscourt victor before completing the victory in two hours 17 minutes.
"He just played better in the decisive moments", Novak Djokovic said.
"I'm very pleased, I needed a match like this".
"Of course I was not at 100 percent today", Nadal, 32, told reporters.
Leading seeds who enjoyed first-round byes swing into action later Wednesday with number one Rafael Nadal starting against Frenchman Benoit Paire with second seed and defending champion Alexander Zverev facing American qualifier Bradley Klahn. "I just played not that great".
Sixth seed Marin Cilic awaits in the quarter-finals following his speedy defeat of Argentina's Diego Schwartzman 6-3 6-2.
In the other quarterfinal, Karen Khachanov of Russian Federation will play Robin Haase of the Netherlands.
He next faces Wimbledon runner-up and fourth seed Kevin Anderson who defeated Ilya Ivashka of Belarus 7-5, 6-3 to also make the last-eight.
Canadian teen Denis Shapovalov went down to Robin Haase, losing 7-5, 6-2, ending local interest.