With his team struggling to score runs and Upton riding a 12-game hitting streak, D-backs manager Bob Melvin decided to move the 21-year-old up to the No. 3 spot in the lineup.
"Why not?" Melvin said before the game.
Upton provided his own answer in the sixth, when he broke open a scoreless game with a missile of a line-drive two-run homer into the seats in left-center field off San Diego ace Jake Peavy.
"That first one, that's a grown man hitting a ball," starter Jon Garland said. "In this ballpark at night, barely getting off the ground off a pitcher like Jake Peavy, that says a lot for him."
Peavy (2-4) had retired Upton in his first two at-bats, the second time getting him to roll over on an outside fastball. The right-hander tried the same strategy in the sixth inning, but did not get the pitch far enough outside, and Upton made him pay.
"He had great stuff and he's always going to pitch you tough, and to be able to get a couple of runs off him is big," Upton said.
The homer came a half inning after Upton saved at least one run with his glove.
Former D-back David Eckstein lifted a fly ball to right with one out and the bases loaded that Upton caught, and he threw a strike to the plate to retire Padres catcher Henry Blanco, who was trying to tag up on the play.
"Upton has to make a good throw ... and he did," Padres manager Bud Black said. "Sometimes, when you're having trouble scoring, you've got to take risks."
"I knew it was going to be pretty shallow, and I had the catcher on third base, so I took my time, got behind it and made a good throw," said Upton.
As a relieved Garland walked off the mound, he noticed something about Upton that indicated something good might be coming from him soon.
"When he's out there defensively and he gets a little bit of that swagger going, feeling good, usually things take over at the plate," Garland said.
Speaking of Garland, the veteran tossed seven shutout innings, allowing just three hits, with the key to his success being that he was able to get ahead of hitters. He was also able to pitch through the four errors that were made behind him.
"I'm just trying to go out there and continue to make quality pitches, regardless of what's happening behind me -- base hits, errors, walks, whatever it may be," Garland said.
It was Garland's second career appearance at PETCO, and he has now allowed just one run in 14 innings at the pitcher-friendly park.
"It's a good ballpark for a pitcher, especially at night, [when] the ball doesn't travel well," Garland said. "So right from the get go, it puts you at ease, as opposed to pitching in a place like Philly, where anything in the air might go out."
Garland used the dimensions of the park to his benefit, challenging the San Diego hitters when he needed to.
"Here it is," Garland said of the thinking. "Hit it and see how far you can hit it. The ball just doesn't travel here."
Unless, of course, it's Upton swinging the bat.
Upton added another homer in the eighth off Duaner Sanchez, this one a solo shot to dead center to put the D-backs on top, 3-0.
Given the way things have gone for the D-backs this year, you had to know it wasn't going to be all smooth sailing.
After setup man Tony Pena retired the Padres in order in the eighth, closer Chad Qualls made everyone in Sedona Red a bit nervous when he loaded the bases in the ninth with nobody out.
Qualls, though, was able to get Blanco to hit into a double play as Adrian Gonzalez scored, and then after walking Luis Rodriguez, the right-hander struck out pinch-hitter Chase Headley to end the game.