"It's a good pitch against a tough pitcher and [Perez] just went down and got it," White Sox manager Robin Ventura said.
The Royals had runners at first and third with one out when Sale made a bid to escape the jam by striking out Alex Gordon. Alcides Escobar stole second and, with first base open, the White Sox decided to intentionally walk cleanup hitter Billy Butler, who had homered earlier.
Perez proved to be up to the challenge and his hit made a loser of Sale for just the second time since May 12.
"When you look at their lineup, Billy is a guy you want to stay away from and you take your chances with Perez," Ventura said.
Sale, 14-4, has been making the critical pitch at the critical time all season. But not Friday.
"[Perez] threw his bat out there and got hold of it," Sale said. "I didn't get it done tonight. The team needed me to be there and I wasn't."
The White Sox had a brief scare in the opening inning when Escobar smashed a ball back to the mound that caught Sale in the left thumb area. But after throwing a pair of warmup pitches, Sale nodded that he was all right.
"It's probably the only spot on him that has a piece of fat, so we were pretty lucky," Ventura said.
Sale gave up a solo homer to Lorenzo Cain in the second, but Paul Konerko, making his return to the lineup after a 10-day absence because of a concussion, answered with his 19th homer in the fourth. The White Sox took a brief 2-1 lead in the fifth when Gordon Beckham came through with an RBI single.
But Butler blasted his 25th homer in the sixth, setting the stage for Perez to be the hero.
"I got outpitched," Sale said. "I've got to be better than that."
The Royals have had starting pitching issues for much of the season, but you wouldn't know it by how they have performed against the White Sox.
"We've said it all along from the beginning of the year: If we get good starting pitching, we feel like we've got a chance to compete every single night," Royals manager Ned Yost said.
Chicago had two hits in the eighth and two in the ninth, but couldn't cash in. Before that, they had just four hits off Mendoza through seven innings.
"He's got a good sinker and a curve he can drop in on you," Konerko said. "His ball moves a lot. The [homer] I hit off him to left was probably the straightest ball he threw all night. That's the one you've got to get because he doesn't throw too many of those. You tip your hat to him. He threw pretty well."
The White Sox (65-53) dropped a game in the standings, but still lead the second-place Tigers by 1 1/2 games.