The Athletics ended a six-game road losing streak.
There have been 25 players in the major leagues with 500 homers and eight have reached that milestone while playing in the Japanese Leagues. Matsui is the first, however, to have a combined 500 homers in both North America and Japan.
His 500th homer was a solo shot in the sixth that gave Oakland a 3-2 lead, but the Tigers took a 5-3 advantage in the bottom half of the inning.
Oakland then scored four times in the seventh, with Matsui's bases-loaded single delivering a run that put the Athletics in front 6-5. He also drove in a run with an infield single in the third, giving him three RBI for the game.
Matsui, 37, hit 332 home runs in Japan before coming to Oakland. He came into the game batting just .175 in his previous 17 games.
Joey Devine (1-1) picked up the win in relief of Brandon McCarthy. Andrew Bailey worked the ninth for his 10th save.
David Purcey (1-2) walked the bases loaded during Oakland's seventh inning and he suffered the loss when all three runners scored.