New York was trailing 2-1 until Nix came up with two outs in the seventh inning and belted the first pitch he saw from Toronto's Mark Buehrle over the left field fence for a score-tying shot.
Then in the ninth, Mark Reynolds drew a leadoff walk from Darren Oliver (3-4). Pinch-runner Ichiro Suzuki went to second on an Edwin Nunez sacrifice, stole third and scored the game-winner on Nix's single to left field.
Mariano Rivera (4-2) earned the decision with scoreless top of the ninth for the Yankees, who took Tuesday's opener 8-4 and notched a fourth straight victory overall.
Rajai Davis went 2-for-4 with an RBI for the Blue Jays.