Nolan Reimold doubled twice and scored three runs, and Vladimir Guerrero knocked in a pair of runs for Baltimore, which picked up just its second win in eight tries.
Jo-Jo Reyes (6-9) earned the win after holding the Tigers to one run on four hits in six innings. It was his first victory in two appearances since the Orioles claimed him off waivers from Toronto on August 2.
"It was good to see him pitch well," said Orioles manager Buck Showalter.
Doug Fister (4-13) was pegged with the loss after giving up eight runs -- six earned -- on 12 hits in 5 2/3 innings. He fell to 1-1 since being acquired from Seattle in a trade last month.
"I go out there expecting to put up zeros every inning and battle every pitch," Fister said. "It's the same mind set."
Baltimore jumped out to an early 2-0 lead in the first. Reimold hit a leadoff single and Markakis followed with a homer to right.
The Tigers came back with a run of their own in the third when Santiago led off the frame by blasting a 3-2 offering over the wall in left.
The O's added three more in the fifth and two in the sixth. In the fifth, Reimold doubled and scored two batters later when Markakis singled to left. Markakis then beat a throw to third on an Adam Jones base hit. Jones took second on the throw before both Markakis and Jones scored on Guerrero's single.
A pair of run-scoring singles from Markakis and Jones in the sixth made it 8-1.
Kevin Gregg struggled in the ninth, surrendering three runs and recording no outs. After loading the bases on three consecutive singles by Victor Martinez, Jhonny Peralta and Ryan Raburn, Gregg issued back-to-back walks to Alex Avila and Santiago. Jackson followed with a single, plating Rayburn and chasing Gregg from the game.
Jim Johnson came on next and retired the first two batters he faced, the second being an RBI groundout by Magglio Ordonez. Johnson intentionally walked Miguel Cabrera to put the game-tying runs on the bases, but Reimold made a running catch on a liner to left by pinch-hitter Brennan Boesch to end the game and give Johnson his second save of the year.