The Blue Jays took a 2-0 lead with a home run by Frank Catalanotto in the first and a Orlando Hudson sacrifice fly in the second.
The Sox cut that lead to 2-1 with a Carlos Lee double, scoring Magglio Ordonez, but after a Paul Konerko double play groundout and Joe Crede fly out to end the inning, the Blue Jays added another two runs with a Shannon Stewart homer and Carlos Delgado RBI-single.
Wright was pulled in the fourth, but not after issuing a leadoff walk to Josh Phelps, who scored on a sacrifice fly later in the inning.
Manuel was ejected in the fifth inning for arguing a call at third base. Crede, who doubled to start the inning, tried to reach third on a Sandy Alomar bunt single. It was the fourth time Manuel was ejected this season.
The Sox will play game two of the set on Tuesday night at 7:05 CT, with Bartolo Colon going against Doug Davis. The game will be televised on WCIU.