Danny Wright started for the Sox, giving up five runs in three innings, while opposing starter Corey Lidle threw a complete game, giving up two runs.
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.
Toronto continued to stack on more runs, scoring one run in the sixth off Dave Sanders, five runs in the seventh off Rick White, and their 12th and final run in the eighth off Gary Glover.
The Sox scored their second and final run in the ninth with a Brian Daubach double, scoring Armando Rios. Frank Thomas singled in the inning before Rios grounded into a fielder's choice.
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.