The 40-year-old Thome hit a two-run homer in the sixth inning for No. 599, then came to bat again in the seventh. He hit a 2-1 pitch from Daniel Schlereth over the fence in left field, then circled the bases as the Detroit fans gave him a standing ovation.
Thome became the second-fastest hitter to reach the milestone, hitting his 600th homer in at-bat No. 8,137. Babe Ruth needed only 6,921 at-bats.
His 64 home runs against Detroit are his most against any team.