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Santiago, who also had an RBI triple among his four hits and scored three runs, put Detroit ahead 8-6 with his homer off Santiago Casilla in the third after trailing 6-0. The Tigers outscored Oakland 34-9 in the weekend sweep.
Landon Powell hit a three-run double and Adam Kennedy homered to help the Athletics build a six-run lead after the top of the second.
Kennedy put the Athletics up 1-0 when his flyball down the right-field line hit the metal base of the foul pole atop the fence in the first for his first homer, and the Athletics added four more runs on Ryan Sweeney's sacrifice fly and Powell's three-double.
Jack Hannahan walked on starter Armando Galarraga's 41st pitch of the inning, and Jim Leyland replaced him with Zach Miner. Galarraga allowed five runs on four hits and three walks, and is 0-3 with a 10.90 ERA in four May starts.
The Athletics made it 6-0 on Sweeney's RBI single in the second, but Santiago answered with a run-scoring triple in the bottom of the inning, and Adam Everett followed with an RBI single to make it 6-2.
Granderson walked, and Josh Anderson hit Detroit's second triple of the inning to cut the deficit to two runs.
Detroit's rally continued in the third, as Gerald Laird's RBI single made it 6-5 and chased Oakland starter Trevor Cahill.
Santiago hit Casilla's second pitch for his third homer, putting the Tigers ahead 8-6.
Orlando Cabrera's first homer of the season pulled the Athletics to 8-7 in the fifth, but Granderson's three-run homer in the bottom of the inning put the game out of reach.
Santiago had a chance at the cycle, but singled to lead off the seventh when he needed a double.
Cahill (2-3) took the loss, allowing seven runs in 2 1-3 innings, while Miner (3-1) picked up the win. The teams each used five pitchers in the game.
Notes: Galarraga became the first major league starter this season to throw more than 40 pitches without surviving the first inning. ... Detroit RHP Jeremy Bonderman, who has been out since last June with a blood clot in his pitching shoulder, is scheduled to make a rehab start for Triple-A Toledo Thursday at Gwinnett. ... Reliever Juan Rincon, who refused a minor league assignment from the Tigers earlier in the week, became a free agent after clearing waivers. ... The Tigers pulled off an unusual 6-5-3 double play in the eighth inning, with Brandon Inge taking the throw at second base because Detroit was shifted for Jason Giambi.
