Boesch collected a one-out single off David Phelps (1-2) in the bottom of the ninth, went to third on Jhonny Peralta's hit and scored the game-winner on Santos' fly ball as the Tigers evened their three-game series with New York.
Miguel Cabrera went 3-for-4 with two solo homers for Detroit.
Tigers starter Rick Porcello held New York to one run on six hits over six innings.
New York's Hiroki Kuroda also pitched well in a seven-inning no-decision, surrendering two runs on seven hits.
Raul Ibanez and Nick Swisher each supplied an RBI the Yankees' loss.