Madison Keys and CoCo Vandeweghe both won their quarterfinal matches in New York on Wednesday, which means the U.S. Open will have an all-American semifinal for the first time since 1981.
Vandeweghe upended top-seeded Czech Karolina Pliskova 7-6 (4), 6-3, while Keys easily got past Kaia Kanepi 6-3, 6-3.
The 20th-seeded Vandeweghe and the 15th-seeded Keys joined two-time champion Venus Williams and fellow American Sloane Stephens in the semifinals after posting straight-sets wins at Arthur Ashe Stadium.
The results guarantee that an American woman other than Serena Williams will be the U.S. Open champion for the first time since 2001, when Venus Williams won her second U.S. Open titles.
None of the top eight seeds remain in the women's draw.
Vandeweghe advanced to her second major semifinal this year, having also reached the final four in the Australian Open in January.
The 25-year-old Vandeweghe will play the winner of Wednesday night's semifinal between Estonian qualifier Kaia Kanepi and No. 15 seed Madison Keys of the United States. If the 22-year-old Keys is victorious, there will be an all-American semifinal lineup at the U.S. Open for the first time since 1981.
Pliskova, who was last year's runner-up at the U.S. Open, will be knocked from her perch as the world's No. 1-ranked player when the new rankings are announced next week. That distinction will belong to Wimbledon champion Garbine Muguruza of Spain.
The emotional Vandeweghe dropped to her knees and held her face in her hands after dispatching Pliskova in one hour, 34 minutes.
"Even though we're out here individually, it's really a team sport," Vandeweghe told the crowd in her post-match interview. "The team works as hard as I do.
"When I won this event as junior at 16, I always dreamed of being on the main stage. It is a process and here I am. I couldn't wish for anything better."
Wednesday's victory was Vandeweghe's second over a World No.1 in her career. She defeated defending champion Angelique Kerber in the fourth round of the Australian Open earlier this season.
Vandeweghe won 81 percent of her first-serve points to keep Pliskova on the defensive, but the former was thrilled with how she reacted to the latter's serves.
"I think there were moments where I was really tough in the big points, and I think my best asset today was making her continually play on her service games," Vandeweghe said. "Whether it was not a great return that just got over the net, I know as a big server it's really annoying when your serve keeps coming back."
In the night match, Keys never seemed to be in trouble against Kanepi, a 32-year-old from Estonia who is ranked 418th. Keys bolted to a 4-1 lead in the first set, and won the first two games of the second to stay in a command against Kanepi, who had defeated Keys in their only previous meeting, in 2015 on clay.
Keys has reached the U.S. Open semifinals for the first time in her career, and she got to the final four of a Grand Slam event for the second time, adding to her semifinal berth at the 2015 Australian Open.