Stephen Drew homered while Josh Reddick and Yoenis Cespedes also drove in runs during the third inning, in which Oakland scored all five of its runs.
Jarrod Parker (11-8) held the Orioles to two runs on seven hits over seven innings, walking one and striking out five as the American League wild card-leading A's won for the eighth time in nine games.
Sean Doolittle hurled a scoreless eighth and Grant Balfour notched his 19th save as Oakland clinched its three-game series.
Zach Britton (5-3) was tagged for five runs on four hits in a four-inning effort for Baltimore, which fell one game behind the New York Yankees atop the AL East.
Nate McLouth socked a solo homer for the O's.