Tiafoe sealed his place in the last 16 of the US Open by defeating 14th seed Diego Schwartzman 7-6(7), 6-4, 6-4 on Saturday.
During his on-court interview after the match, Tiafoe lavished praise on Serena Williams, calling her an "absolute icon" and "the biggest inspiration."
"What she did for the game is unbelievable," Tiafoe said. "What she did for me is unbelievable, and for so many others. She is an absolute icon. When you say her name, you say Michael Jordan, you say Tiger Woods, you say LeBron James. She is unbelievable, She is unbelievable, she is the biggest inspiration honestly."
The 24-year-old said that Williams was "one of the best athletes of all time" and credited her for his success in the sport.
"She is not one of the best female athletes, she is one of the best athletes of all time. And, you know, I love her with everything and I hope that's not the last time we all see her play the game of tennis. But there would be no Frances Tiafoe without Serena Williams," Tiafoe added.
After his victory over Schwartzman, Tiafoe set up a clash against Rafael Nadal in the fourth round of the US Open.
Serena Williams lost in the 3rd round of the US Open
Serena Williams reached the third round at the US Open with wins over Danka Kovinic and World No. 2 Anett Kontaveit. However, her hopes for a 24th Major were dashed by Ajla Tomljanovic in a thrilling match that lasted three hours and seven minutes.
In her post-match press conference, Williams left some ambiguity regarding her retirement, saying she wasn't sure whether this was indeed her last match and that she "always did love Australia."
"I don't know. I'm not thinking about that," she said. "I always did love Australia, though. But yeah, you know what, I've come a long way since last year at Wimbledon. Just not sure if that was my last moment or not. Making it a different moment I think is much better."