The loss cut the Royals’ lead to a half-game over Detroit in the AL Central.
Santana connected in the ninth inning for his 22nd home run, helped Cleveland win for the fifth time in six games.
Boosted by his big four-game set in July, Santana is 14 for 26 with six homers, 13 RBIs and a 1.269 slugging percentage this year in Kansas City.
Danny Salazar (5-6) pitched four-hit ball for five shutout innings. He didn’t come back out after a 44-minute rain delay in the bottom of the sixth.
Jason Vargas (10-7) gave up 10 hits and four runs in six innings. In his past two starts, both losses, he has allowed 21 hits in 12 innings.