Mark Reynolds hit a solo homer and Luke Scott added an RBI single in the five-run fifth as the Orioles won their third straight against the reeling Chisox and their fifth in six games overall.
Scott also connected for a solo homer, backing Zach Britton (5-1), who yielded only one run on five hits over six frames, walking three and striking out one.
Kevin Gregg put out the fire with his fifth save after the White Sox had scored three times in the late innings to make it close.
Gavin Floyd (3-2) was lit up for six runs on seven hits in a six-inning start as the Chisox dropped their fifth straight and 16th in 20 games.
Brent Lillibridge hit a bases-empty homer and Adam Dunn added a pinch hit, two-run shot for Chicago.