Thome finished 3-for-4 with a pair of home runs -- including his 600th career blast -- and drove in five as Minnesota rolled to a 9-6 win in Monday's opener.
The historic blast came in the seventh inning off Tigers left-handed reliever Daniel Schlereth. The 40-year-old became the eighth player in baseball history to reach the milestone, and the first since Yankees third baseman Alex Rodriguez last season.
"I'm a huge fan of his," Schlereth said when asked how he felt to be on the opposite side of history. "He did a great thing tonight. I felt kind of awkward ... I didn't know whether to clap or what. I didn't know what to do. I'm probably going to write him a letter and congratulate him on his accomplishment."
Thome entered play with 598 career homers, and hit his first of the contest -- a two-run blast to left -- in the sixth inning off Detroit starter Rick Porcello.
"I envisioned doing this in Minnesota, amongst the home fans. But to do it anywhere is great," said Thome. "To do it in a Twins uni is just very cool. In a visiting park, they give you a standing ovation is just cool. To watch them stand up and cheer is very special. (It's) something I'll never forget."
Ben Revere added two hits and two RBI for the Twins, who won for just the second time in their last 10 games.
Victor Martinez hit a two-run home run, Ryan Raburn added a solo homer and Alex Avila finished 3-for-4 and a home run short of the cycle for the Tigers, who have lost two in a row following a three-game win streak.
Delmon Young, acquired by Detroit prior to the game from Minnesota for pitcher Cole Nelson and a player to be named later, also went deep in the setback.
It didn't help Porcello (11-8), who was tagged in defeat for nine hits and six runs -- four earned -- over six full frames.
Remaining in the win column may prove to be difficult for Minnesota tonight, as the Twins will be going up against Justin Verlander, who has been the best pitcher in baseball this season and will be trying for his major league- leading 18th win of the year.
Verlander won his fifth straight start on Thursday in Cleveland, holding the Tribe to three runs and three hits in seven innings. He also struck out 10 and improved to 17-5 on the year to go along with a 2.35 ERA.
The right-hander gave up a run in eight innings to beat the Twins the last time he faced them and is 8-7 lifetime against them with a 3.55 ERA in 19 starts.
Minnesota will counter with righty Nick Blackburn, who is 7-9 with a 4.36 ERA. Blackburn has lost his last three decisions but did not get a decision on Wednesday against Boston despite a terrific effort that saw him surrender just an unearned run in 6 2/3 innings of a 5-2 win.
Blackburn has faced the Tigers 12 times (10 starts) and is 4-5 with a 5.03 ERA.
Detroit has handled the Twins this season, taking eight of the 10 matchups, including three of the four in the Motor City. Dating back to last season, the Tigers have won six of seven at home in the series and 12 of their last 14 overall.