Gonzalez's shot and a strong outing from starter Wade LeBlanc helped the Padres to a 7-1 win over Seattle on Saturday night, the Mariners' fifth straight loss.
The home run by the streaking Gonzalez came after LeBlanc escaped a bases-loaded, no-out jam in the top of the first.
"I think everybody in this stadium can sense a shift after Gonzo's homer," LeBlanc said. "It's huge, especially against a guy like Cliff Lee. If you can get some early runs, get to him early because once he settles down, it's tough."
Lee (4-3) proved that by retiring the final 11 batters he faced.
But LeBlanc (4-4) provided his club with a big boost in the first by first getting Jose Lopez to ground into a third-to-home-to-first double play. After intentionally walking a batter to load the bases again, the left-hander retired Josh Wilson on a fly ball.
"That was huge," Gonzalez said. "It just picks you up, especially in the first inning. Everyone is trying to get into the groove of the game and something like that just gets you going."
Said LeBlanc: "That's not the ideal way you want to start off the game but that's the way it happened. Fortunately, everything worked out."
Oscar Salazar added a pinch-hit three-run shot, his first home run of the season, to break open the game in the eighth.
It added up to Seattle's eighth loss in nine games. It also led to a Mariners' players-only meeting after the game.
"We have to turn it around," Lee said. "It's about time to snap out of it, but it is what it is. We've got to do a better job of executing, and that's everybody."
The Mariners tied their season high by stranding 12 runners. Seattle also loaded the bases with one out in the eighth off Mike Adams. But Adams retired consecutive pinch-hitters, striking out Michael Saunders and getting Casey Kotchman on a grounder.
"That's two nights in a row that we've had a pretty good starting pitching performance and our offense has squandered it," Seattle manager Don Wakamatsu said. "We came out of the gate early and aren't able to score. With Cliff Lee on the mound and the way he's been pitching, it's a totally different ball game."
Over his last 13 games, Gonzalez is batting .412 (21 for 51) with five homers, 15 RBIs and 10 runs scored. He is 7 for 9 against Lee, including seven straight hits.
Gonzalez's first-inning home run was only the second surrendered by Lee this season.
"I got behind 2-0 there and threw a cutter and he hit it out," Lee said. "He's a great hitter. For whatever reason, I've had trouble against him."
LeBlanc pitched his second strong game after a four-game losing streak. The lefty got through six innings, allowing one run on seven hits and stranding eight baserunners.
Lee gave up three runs and seven hits in seven innings.
With the win, the Padres clinched the season series over Seattle for the first time since 2004.
"We lost another game and the frustration is really growing even more at this point," Wilson said. "We've got to do something to break it."
Gonzalez's homer was his 14th this season, but just five have come at Petco Park.
Salazar has five career pinch-hit homers. ... Lee had worked at least eight innings in his previous three straight starts, including a complete-game win in his last start. ... San Diego won its second straight interleague home game after having lost 12 of their previous 14 coming into the series. ... Seattle LHP Luke French, recalled from Triple-A Tacoma on Sunday, will replace struggling RHP Ian Snell in the starting rotation. ... Padres bench coach Ted Simmons was the interim manager while Bud Black attended his daughter's graduation on Saturday from Oregon State.