The Orioles had lost three in a row and began the night 1 1/2 games out of a playoff position, but Baltimore overcame a three-run deficit against the Blue Jays.
J.J. Hardy started the comeback with an RBI double in the seventh and then scored along with Ryan Flaherty on a double from Steve Clevenger that tied the game.
Davis put the Orioles in front by leading off the eighth with his milestone home run. He began the night having hit seven more homers that Detroit's Miguel Cabrera, a statistic that if it holds up to the end of the season will likely be the cause of Cabrera not winning his second straight triple crown.
The 50 home runs are 17 more than Davis has ever had in a season.
Danny Valencia singled in an insurance run later in the eighth.
The loss went to Steve Delabar (5-4), who gave up the home run by Davis.