Thome's home runs were his only hits of the night as the veteran slugger went 2 for 3 with four RBIs and two walks while hitting out of the No. 6 spot.
Thome missed 19 games with a left oblique strain and was activated from the disabled list after Sunday's loss to Arizona.
His first home run of the night came against Mariners starter Jason Vargas in the fourth and traveled 465 feet while Thome's second shot -- the 593rd of his career -- was a low liner in the seventh against reliever Aaron Laffey.
"You go on the DL and you go down, you always want to come back and swing the bat well," Thome said. "Unfortunately, we didn't win the ballgame. That's what you want to do every night. It felt good to swing the bat good, but ultimately, it's all about winning."
While Thome has returned, Minnesota is still without its biggest star.
The Twins say All-Star catcher Joe Mauer could be be the designated hitter in an extended spring training game this week. He's been out since April 14 with leg weakness.
An MRI exam on Kevin Slowey's oblique did not reveal any damage, but the righty wasn't available Monday.
The experiment of using Slowey out of the bullpen may be finished. He told manager Ron Gardenhire over the weekend that he would like to start, which means he could be sent to Triple-A Rochester or traded.
Information from The Associated Press was used in this report.