Santana, who finished 16-8 with a 3.28 ERA in 211 1/3 innings, will start Tuesday's American League Wild Card Game, likely against the Yankees in the Bronx at 7 p.m. CT on ESPN. New York is expected to counter with right-hander Luis Severino if it doesn't win the AL East.
"It was a nice tuneup performance from him," Twins manager Paul Molitor said. "Hopefully it gets him ready for Tuesday."
The Twins pushed up Santana by a day to have him start on regular rest on Tuesday, and they limited his pitch count to keep him fresh. Santana was efficient against the high-powered Indians, scattering four hits while needing 57 pitches to get through the five scoreless frames.
"I felt good," Santana said. "Everything was working like I wanted. The location was good. The offspeed was good. So no complaints."
Santana posted the second lowest ERA and the second highest win total of his 13-year career. He struck out 167 and walked 61. He also limited hitters to a .225 average.
"The ERA is always one of the indicators you can measure, and sub-4.00, you're having a nice year," Molitor said. "He ended up over 210 innings. His batting average against -- just a lot of things that showed he was out there taking the ball as well as giving us consistency and a chance to win."
Santana recently pitched at Yankee Stadium, allowing two runs over 5 2/3 innings in a loss on Sept. 18. But he's pitched well down the stretch, with a 3.31 ERA in six September starts.
"The big thing for me was staying healthy all year," Santana said. "But we still have a long way to go."
Santana, an All-Star for the second time in his career this season, has pitched in the postseason before, but not since 2009. Santana is 2-2 with a 5.56 ERA in eight appearances (two starts) in five playoff series, all with the Angels.
Santana's best postseason results came in relief against the Yankees, when he got the win in Game 5 of the ALDS in 2005, allowing three runs over 5 1/3 innings. He also posted a 1.59 ERA in four appearances in the '09 ALCS. He has a career 3.27 ERA in 11 innings against New York in the postseason, but Brett Gardner is the only holdover from the last time he faced the Yankees in October.
Santana believes his experience will help him, but said the key mentally is not making the start any bigger than it is.
"I'm very excited, but I take it day by day," Santana said. "To me, I'm going to take it like another game. I'm not going to think about it. I'm just going out there and pitch my game. I'm not going to change my approach."