Overbay's clout off Mark Hendrickson (1-6) made a winner of David Purcey (1-1), Toronto's seventh pitcher, who had thrown a scoreless top of the 11th.
The Blue Jays socked four homers in the game, including blasts by Travis Snider, Aaron Hill and Edwin Encarnacion, clinching their three-game series with the O's at Rogers Center.
Toronto starter Rickey Romero lasted five innings, yielding three runs on five hits.
Ty Wigginton homered and the O's scored a pair of first-inning runs on bases-loaded walks in the loss.
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