Bautista sent an 0-1 pitch from Baltimore's Brad Bergesen over the center-field wall in the first inning. The drive landed in the bullpen and gave the Blue Jays a 1-0 lead.
It was his seventh of the season off the Orioles, the most against any team. It was his second off Bergesen.
Bautista began the year with 59 career homers.
Toronto has hit at least one home run in 17 consecutive games, the longest run in the AL this year and one short of the streak of 18 straight by the Cincinnati Reds from May 11-29.