Felix Hernandez (12-12) allowed only two hits over eight innings but the first was Bautista's first-inning, two-out blast over the wall in left field.
Hernandez walked the next two batters but then retired the next 13 before yielding a lead-off single to Travis Snider in the sixth. He also walked four and struck out five.
Toronto starter Shawn Hill (1-2) collected his first win with the Blue Jays, lasting five innings and giving up four hits and walking one. He also struck out seven. Kevin Gregg pitched the ninth and earned his 35th save.
Bautista, in his seventh major-league season, had never hit more than 16 home runs in a season prior to 2010. He is the first player to reach the 50-home-run mark since Alex Rodriguez (54) and Prince Fielder (50) hit that many in 2007.
The final hit allowed by Hill Thursday was a single by Ichiro Suzuki in the fifth inning. That allowed the Seattle outfielder to reach the 200-hit mark for the 10th consecutive season, extending his own record for consecutive years with at least 200 hits.
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