Kyle Seager hit a three-run homer in the first inning, Brad Miller added a solo shot, and Seattle's Chris Young threw six shutout innings against his former team.
Gwynn died earlier Monday of oral cancer, a disease he attributed to years of chewing tobacco.
San Diego was shut out by Young (6-4) and a pair of relievers until Carlos Quentin hit a solo homer leading off the ninth.
Seager's homer came on a 3-0 pitch from San Diego starter Tyson Ross (6-6). Coming off a 4-for-4 performance on Sunday, Seager was given the green light and hit his 10th homer of the season. Miller followed with a solo homer an inning later.
Robinson Cano added an RBI double as Seattle scored all five runs in the first two innings.
But Gwynn was on everyone's mind at Safeco Field. Seattle honored Gwynn with a video tribute and moment of silence before the game and put a '19' on the dirt in the hole between the shortstop and third baseman. Gwynn called that the "5.5 hole" and many of his 3,141 hits went through it.
San Diego added black armbands to its uniform in honor of Gwynn, and his No. 19 jersey hung in the Padres dugout. His jersey also was scattered among fans in attendance.
Seager leads Seattle in home runs and has seven hits in his last 10 at-bats with six RBIs. James Jones also stole three bases and scored twice for Seattle.
Young was once an All-Star for the Padres and has become a valuable acquisition since joining Seattle at the end of spring training. After losing his last two starts, Young gave up two hits in the first inning and then cruised. He retired 16 of the final 19 batters he faced, giving up a pair of singles and issuing one walk. He matched his season high with six strikeouts.
Joe Beimel, who gave up the final home run in Gwynn's career, pitched one inning of relief for Seattle. Tom Wilhelmsen then got the final six outs, but couldn't complete the shutout giving up Quentin's third homer of the season.
Ross had allowed only one homer in his previous six starts, but struggled all night. He walked a career-high seven and at least one in every inning. Ross pitched into the sixth inning and helped save the Padres bullpen.
NOTES: Young has now faced every team in the majors. ... Seattle hopes to send injured 1B Justin Smoak (quad) out on a rehab assignment Wednesday. Corey Hart (hamstring) and Michael Saunders (shoulder) could join Smoak on rehab assignments by the end of the week. ... In 11 career games against Seattle, Gwynn hit .261 (12 for 46) with three doubles and four RBIs.