Tsitsipas was favored in the match, having come in second to Novak Djokovic in the French Open final earlier this month.
"Definitely one of my best [matches]," Tiafoe said in his on-court interview after the win.
"From start to finish, it was pretty clean," Tiafoe said. "If you want to play against the [best] players in the world, this is what you train for."
Tiafoe, 23, had never beaten an ATP top-5 player, and his victory makes him the youngest American man to defeat a top-5 player at a major since 21-year-old Robby Ginepri defeated world No. 5 Juan Carlos Ferrero in the third round of Wimbledon in 2004.
The 57th-ranked Tiafoe is also the first American man to knock off a top-three seed at a major in straight sets since Andy Roddick bested Ferrero in the final of the 2003 US Open. Roddick's victory was the last time an American man won a major.
Tiafoe has never made it past the third round of the singles at Wimbledon, but he looked confident against Tsitsipas. He immediately broke to open the match, then built on his early good form and never let the 22-year-old from Greece gain control.
"Today was big, and I definitely needed that," Tiafoe said.
Monday's win continues a stretch of good play from Tiafoe that has included a trip to the quarterfinals at Queen's Club and a title at the Nottingham Challenger tournament.
"There's been a lot of things going on recently for me. I've made a lot of changes," Tiafoe said. "I haven't even scratched the surface."
"Fair to say he played really well," Tsitsipas said. "I wasn't able to maintain the intensity. I wasn't able to put something better than him. It ended up going his way."
Tiafoe acknowledged that Tsitsipas has a bright future ahead of him, even if it wasn't fully on display Monday.
"That guy is special. He's going to do a lot of great things. Win a ton of Grand Slams," Tiafoe said before breaking into a smile. "But not today."