The game was tied at five through the first four innings, and in the bottom of the fifth Jed Lowrie hit an RBI double to put Houston up 6-5.
But three innings later the Padres grabbed the lead on a three-run home run from Jesus Guzman.
The back-and-forth affair continued in the bottom of the inning when Jason Castro tied the game on a home run for the Astros.
But Houston's resiliency was for naught as Quentin's double off Lyon won the game for Padres in the 10th inning.
The Astros will look to bounce back on Tuesday when Jordan Lyles (1-4, 5.04 ERA) takes on Kip Wells, who is making his first MLB appearance since 2009.