Stewart, who entered during a double switch in the 10th, drove a 2-0 pitch from Tim Stauffer into the seats in left-center, his fifth. Most of the crowd of 17,121 was gone by the time the game was decided.
"That's a terrific at-bat right there," manager Jim Tracy said. "To hit the ball where he hit it, at this late an hour, with the air as heavy as it was, at this early a juncture of the season, gives you a pretty good idea of how hard that ball was hit."
Stauffer left a changeup over the plate.
"I hit it good," Stewart said. "It's tough to hit the ball out here, anywhere, especially to right, and even to left. But you surprise yourself sometimes. I feel good about it."
Stauffer "got behind and elevated it," manager Bud Black said. Stewart, the manager added, "has all-field power."
The loss dropped the Padres percentage points behind the San Francisco Giants in the NL West. San Diego had won its previous five series, including two sweeps.
The home run ended Stauffer's streak of 17 1/3 scoreless innings to open the season. Stauffer (2-1) had been the only major leaguer to have pitched at least 15 innings this year without allowing a run.
The Padres had runners on first and second with two outs in the 10th before Manny Corpas (1-1) got Kyle Blanks to fly out to right. Corpas pitched the final 2 2/3 innings.
Blanks reached second with two outs in the eighth after a strikeout, wild pitch and an error on catcher Miguel Olivo. Blanks swung and missed at Rafael Betancourt's pitch that was in the dirt and got away from Olivo. Blanks hustled to first and Olivo's throw was wide and caromed off the front of the stands and into short right. Blanks slipped and fell rounding first but got up and had time to pull into second base standing up.
After all that, he was stranded when Jerry Hairston Jr. struck out.
Clint Barmes had three hits and three RBIs for the Rockies. Blanks had two RBIs for San Diego.
The Padres went ahead 5-3 with a four-run fourth highlighted by left-hander Clayton Richard's two-run double with two outs. Richard had given up three runs in the third inning as the Rockies took a 3-1 lead.
Richard threw 103 pitches through five innings and was replaced by Edward Mujica opening the sixth. Mujica walked Olivo and gave up an RBI double by Barmes, followed by an RBI triple by pinch-hitter Seth Smith, both into the right-center gap, as the Rockies pulled into a 5-5 tie.
Richard struggled through the third, giving up three runs on three singles and two walks. Melvin Mora drew a one-out, bases-loaded walk and Barmes hit a two-run single to left for a 3-1 lead.
"It didn't go like I planned it," Richard said. "But you have to find another way and adapt. I finally got settled in and was able to keep us in the game."
Colorado's Aaron Cook gave it all back in the fourth, when the Padres rallied for four runs on four hits and a walk. Blanks hit an RBI single over shortstop Troy Tulowitzki, Hairston Jr. followed with an RBI single to left to tie it and Richard put the Padres ahead with an opposite-field double that sliced past left fielder Eric Young Jr.
Richard allowed three runs and six hits in five innings, struck out five and walked five. Cook also went five, allowing five runs and six hits, with two strikeouts and two walks.
Blanks hit an RBI double in the second.
Rockies closer Huston Street, on the disabled list with inflammation in his right shoulder, is scheduled to pitch an inning in an extended spring training game on Saturday. Manager Jim Tracy said Street is scheduled to return to Denver on Monday to be re-evaluated, and if all goes well, could be sent out that day on a rehab assignment. ... Padres SS Everth Cabrera, on the DL with a strained right hamstring, took batting practice and grounders. The only running he's been able to do has been in a pool.