With Santana hoping to build on another solid offensive night at Kauffman Stadium, the surging Indians try to hand the Royals a third consecutive defeat and keep James Shields from winning a fourth straight start against them on Saturday night.
Winners in 12 of 17 following Friday's 6-1 victory, third-place Cleveland (69-64) is 4 1/2 games behind Kansas City, which has totaled 16 runs while losing four of six.
Santana hit a two-run shot for his sixth homer in the last four games at Kansas City. He's homered in each of those four, and is batting .442 with seven home runs and 14 RBIs during an 11-game overall hitting streak against the Royals (74-60) this season.
''I hope the streak continues,'' Indians manager Terry Francona said. ''That's a nice swing. He can get streaky with his homers.''
Santana has totaled 13 of those RBIs while going 14 for 26 in seven games at Kansas City.
''I have teams, Minnesota, Kansas City, I have good sense when I come here,'' he said.
Santana is batting .276 with a home run and two doubles in 29 at-bats versus Shields (12-7, 3.45 ERA), who has a 1.80 ERA with 26 strikeouts over 20 innings in his last three starts versus Cleveland. He gave up an earned run and fanned nine in six innings of an 8-2 win at Cleveland on April 22.
The right-hander posted a 2.04 ERA while going 4-2 over a nine-start stretch prior to giving up six runs and 10 hits in 6 2-3 innings of an 8-1 home loss to the New York Yankees on Monday.
"For the last month or so, I think I've been pitching pretty well, for the most part," Shields told MLB's official website. "I had a little hiccup (Monday), but that's part of the game."
Kansas City's Alcides Escobar had four hits Friday after going 3 for 22 in his previous six contests. He's 11 for 24 against the Indians at home this season.
Though Cleveland's Trevor Bauer (5-7, 4.18) is 4-2 with a 3.07 ERA in 11 home starts, he's 1-5 with a 5.81 ERA in nine road contests.
The right-hander allowed five runs in 4 2-3 innings of a 7-5 win at Minnesota on Aug. 19, then rebounded by giving up four hits and striking out nine in six-plus scoreless innings of a 3-1 home victory over Houston on Sunday.
''He'll go through spurts where he throws three or four balls in a row, but you look up and he's throwing a lot of strikes,'' Francona said. ''He has periods where he kind of loses what he's doing, but he really competes. He gets mad at himself when he doesn't do what he wants.''
In Bauer's only other outing against the Royals on June 11, he gave up three runs in 5 1-3 innings of a 4-1 loss at Kauffman Stadium.
Omar Infante is 0 for 2 against Bauer, and could be available after missing four straight contests with a sore shoulder.
He's 0 for 11 in his last three home games versus Cleveland.