Kaz Matsui hit a solo homer for the first of four straight hits in the first inning off Santana, who struck out one and walked one.
The left-hander made it through the short outing with no setbacks as he continues to build strength following Sept. 1 surgery to remove bone spurs from his elbow. Santana had reached his pitch count when he was pulled from the game.
"They made me work today," said Santana, who threw 33 of 47 pitches for strikes. "They were swinging right away, but I feel good because I was able to throw all my pitches. I was a little off with my mechanics and release of the ball, but that's part of spring training. That's what we are here for, trying to make adjustments and throw my pitches. The good thing is I felt good. I didn't feel any problems with my arm."
The two-time Cy Young winner said he held back some in his first outing but was glad to be back in a live game.
"Mentally you feel good because that's one of the big steps you have to make to finally get into a real game and see how your arm reacts to that surgery," Santana said. "Overall, I felt pretty good."
Astros right-hander Brett Myers, the former Phillies ace who is projected as the No. 3 starter in Houston, showed progress in his second outing of the spring. Continuing to work on his slider, he gave up two runs on four hits in three innings, including a two-run homer to David Wright in the first. Myers struck out one and walked one.
"The first inning I struggled a little bit trying to make an adjustment to the mound and the things we worked on in the bullpen," Myers said. "You go from different mound to different mound, and it just took me a little longer than I wanted to make the adjustment."
Pedro Feliz, another free agent pickup from the Phillies, hit a two-run homer for Houston.
Mets first base prospect Ike Davis, a first-round draft pick in 2008, continued to impress with his second home run of the spring in the seventh inning. He likely will start the season in the minor leagues, but manager Jerry Manuel wants a good look at him in camp.
"He has a real fluid, powerful swing, and you've got to give him some thought when that kid hits the ball out to center field, grand slams and so forth," Manuel said.
NOTES: The Mets reassigned catchers Francisco Pena, Kai Gronauer and Mike Nickeas to minor league camp Tuesday. ... SS Jose Reyes remains in New York while awaiting test results on a possible thyroid imbalance. He is not expected back for a couple of days.