Thome went 2 for 4 with a double and three RBIs, leading the Twins past the Tampa Bay Rays 12-3 on Sunday.
The Twins sent out their opening day lineup, with Thome spelling Jason Kubel as the designated hitter with Kubel playing in an intrasquad game, and tagged Rays starter Wade Davis for five runs in the first inning.
Davis, trying to earn a spot in Tampa Bay's starting rotation, gave up seven runs -- five earned -- in two innings. He walked one and struck out one.
"I had one goal, and that was to try to pitch all my innings," Davis said. "That didn't happen. I think I can do a lot better against them. I know I can do a lot better."
Scott Baker, already named the Twins' Opening Day starter, struck out three, walked one and gave up one hit in five innings.
Joe Mauer went 2 for 4 with a run scored, boosting his spring training batting average to .471 before the team announced his agreement on an $184 million, eight-year contract extension.
"I wrote the lineup because I like the lineup," manager Ron Gardenhire said. "I had anticipated that it was going to be a very good day swinging the bats with that lineup."
Thome, who signed a one-year, $1.5 million contract to be a pinch hitter and fill in for Kubel, hit a two-run double off the right-field wall and boosted his spring average to .333.
The 39-year-old Thome later looked like he was laboring as he crossed home plate to score. Asked about his speed, Gardenhire smiled.
"He's run a lot of times around those bases," Gardenhire said. "Most of the time, that's as fast as he has to run. That's why we have to keep one extra guy on the bench, to get that run in if we have to."
With 564 career home runs, Thome ranks 12th on baseball's all-time list, trailing No. 11 Rafael Palmeiro by five and No. 10, former Twins slugger Harmon Killebrew, by nine.
Gardenhire said he has been impressed by Thome's work ethic.
"He has been hitting the ball pretty hard," Gardenhire said. "He gets here really early and does a lot of work on his body and his back. I think health is the No. 1 issue, getting through spring training and getting him enough at-bats."
Thome's back flared up after a three-hour bus ride back from Clearwater last week. But the back has calmed down, and Gardenhire has decided on a solution in preventing that from happening again.
"We're going to try to have him stay away from bus trips," Gardenhire said.
Twins RHP Nick Blackburn threw four innings in an intrasquad game, and Gardenhire said that Blackburn's sore knee feels better. He will start on Saturday.