A day after top seed Daniil Medvedev was bundled out of the tournament, Tsitsipas was sent packing 2-6, 6-3, 6-4 on the Hard Rock Stadium's Grandstand Court in 2hr 20min.
It means that Russia's fourth seed Andrey Rublev, who plays Sebastian Korda later Thursday for a place in the last four, is the highest seeded player left in the tournament.
Tsitsipas exited the tournament after a tense encounter that saw the 22-year-old Greek given a time violation after the second set for taking too long to change his shirt and headband.
The world number five was also reportedly involved in a tense exchange with officials before the match after refusing to share a golf cart with Hurkacz used to ferry players to the court.
There was no sign that incident had unsettled Tsitsipas early on, however, as he dominated a one-sided first set to win 6-2.
Tsitsipas then quickly broke Hurkacz at the start of the second on the way to a 2-0 lead.
But just when it appeared the match was heading for a brisk conclusion, Hurkacz finally found his range.
After staving off two break points at 15-40 in the third game, Hurkacz went on to hold and then broke to level the set at 2-2.
Another break of serve in the eighth game put Hurkacz 5-3 up and he made no mistake on his next service game, clinching the set with an angled drop shot that left Tsitsipas scrambling to the net.
Tsitsipas demanded an appearance from the tournament supervisor at the end of the second set after being given a time warning by the umpire.
The momentum was with Hurkacz in the third and seized control with a break in the fifth game, which would ultimately prove decisive as the Pole closed out the win.