NEW YORK — Jessica Pegula caused a huge upset at the US Open by defeating Iga Swiatek, 6-2, 6-4, to reach her first Grand Slam quarterfinal in her seventh attempt.

Her victory ensures that multiple American men and women will play in the US Open semifinals for the first time since 2003 (Andre Agassi and Andy Roddick; Lindsay Davenport and Jennifer Capriati).

Swiatek served poorly in the first set and her forehand was a real problem, with 22 of her 41 unforced errors coming on that side. Pegula used great defense to keep forcing Swiatek to hit the extra shot.

Sixth-seeded Pegula, a 30-year-old American, has won 14 of her last 15 matches and will make her Grand Slam semifinal debut on Thursday against unseeded Karolina Muchova of the Czech Republic.

Pegula repeatedly did what had recently seemed nearly impossible against Swiatek, who counts the 2022 US Open among her five Grand Slam titles and has led the WTA rankings for the past 2½ years: break her serve.

Up until Wednesday, Swiatek had lost only two service games in four matches at the hardcourt tournament, both in the first round. She had also not faced a single break point in her last three matches.

But Pegula, whose parents own the Buffalo Bills (NFL) and Buffalo Sabres (NHL), didn’t have much trouble with that, especially early on. He broke in each of Swiatek’s first two service games, both of which ended with a double fault, and in three of the first six.

It helped that Swiatek couldn’t fine-tune her first serve early on. She had only 2 out of 12 serves (16.7%) in play at the start, compared to just 36% in the first set.

Pegula entered the day as the only player in the WTA’s top 10 who had not reached a major tournament semifinal. She was 0-6 in her career in Grand Slam quarterfinals, one loss shy of the worst major tournament quarterfinal record by a woman in the Open Era, shared by three players (0-7).

During that 0-6 streak, the players were eliminated twice by Swiatek and once by another number 1 player, Ash Barty.

Pegula was asked about that record this round during her post-match interview on the court after winning her fourth-round match. And again during the press conference that followed. And again during a TV interview before she entered Arthur Ashe Stadium on Wednesday.

If that bothered her, Pegula didn’t show it. Just as she showed no discernible emotion after leading 4-0 after just 21 minutes in the quarterfinals. Even when Pegula took that set, there was only a slight tremor in her left fist as she walked to her seat on the sidelines.

Swiatek couldn’t hide her frustration, including a hard blow to her right thigh after a forehand flew wide and was broken again, and trailed 4-3 in the second set. Fifteen minutes later it was over.

Before Pegula, the last American woman to defeat a world number one at a major tournament was Shelby Rogers, who defeated Barty in the third round of the 2021 US Open.

Entering Wednesday, Swiatek held a 6-3 lead in her head-to-head matchups with Pegula. Their last meeting came at the WTA Finals in Cancun, where Swiatek defeated Pegula 6-1, 6-0 in the most lopsided championship match in the history of the year-end event.

ESPN Stats & Information and The Associated Press contributed to this report.