Thome helped the White Sox go ahead 8-to-2 in the fourth with his ninth homer of the season. He leads all players with 53 career interleague homers.
Pierzynski had three of the Chisox's 13 hits, including a pair of run-scoring singles.
White Sox outfielder Jermaine Dye made two diving catches but had to leave the game as a precaution in the fourth inning with a strained right quadriceps.
Jose Contreras pitched into the seventh to get the win, giving up five runs and eight hits to improve to 5-and-7.
Bobby Jenks picked up his 18th save by closing out Chicago's fifth victory in 22 games.
Josh Johnson was pounded in his first start since coming off the disabled list, yielding eight runs, four earned, and nine hits over three and two-thirds.