Thome led off the fourth inning for Baltimore on Friday night and connected off Cleveland's Derek Lowe. It was the 41-year-old's first homer since being acquired by the Orioles from the Philadelphia Phillies on July 1, and sixth of the season overall.
It was Thome's 189th homer at Progressive Field. He played for the Indians from 1991 through the 2002 season and returned for the final two months of 2011.
Thome holds the Indians' record with 337 homers. He has also played for the Chicago White Sox, Los Angeles Dodgers and Minnesota.