The Orioles were trailing 3-1 in the seventh, but Indians starter Justin Masterson hit Adam Jones with a pitch to lead off the frame Chris Davis followed with a game-tying, two-run shot, his MLB-best 28th of the year.
Baltimore then put two more runners aboard with two outs and Casilla, hitting .216 for the season, belted a 1-1 pitch into the right field stands for the decisive blow as the O's notched a fifth straight win.
Chris Tillman (9-2) posted his fifth victory in five starts, limiting the Tribe to three runs on four hits over seven innings. The right-hander overcame four walks and fanned six.
Masterson (9-6) was tagged for six runs on six hits over 6 1/3 frames.
Jason Kipnis went 2-for-2 with a two-run homer and a pair of walks for Cleveland.