The Astros ended an eight-game losing streak.
Juan Gutierrez (0-4) came on to work the ninth for the Diamondbacks and he threw a mere six pitches before Lee brought an end to the game.
Kazuo Matsui drew a leadoff walk and Lee, batting just .198, then hit the first pitch he saw over the wall in left field. It was Lee's first homer of the season.
The win went to Matt Lindstrom (1-0), who put runners on first and second with one out in the top of the ninth before getting Kelly Johnson to ground into a double play to end the inning.
Houston's other two runs came on a home run by Tommy Manzella in the second. Arizona had won the first two games of the series.