That ended a three-game losing streak for the Phillies (15-18), who had lost five of their previous six games.
Ruiz's home run was his sixth of the season, matching his total from all of last year when he had 410 at-bats. This season he has 94 at-bats.
The 33-year-old Ruiz is not that far off his career high of nine home runs in 2009. Ruiz is now batting .340 with 22 RBIs.
He has been bothered by a sore hand, but it didn't show against the Padres.
"Chooch was outstanding tonight," Manuel said. "He has been hitting the ball to all fields, he's really seeing the ball."
The Phillies took a 2-0 lead in the second inning when Ruiz legged out an infield single prior to John Mayberry Jr.'s two-run home run to left. It was Mayberry's first home run this season. He had gone 88 consecutive regular-season at-bats without a home run, including 71 this year.
Last season, Mayberry had 15 home runs in 267 regular-season at bats for the Phillies.
"It was good to get off the goose egg," Mayberry said.
San Diego entered the game with the second-lowest run total in the National League, 102. The Padres tied the score with two runs in the fourth on RBI singles to left by Yonder Alonso and Jesus Guzman.
Ruiz broke the tie and put the Phillies ahead to stay with his two-run blast in the bottom of the inning.
"Chooch looks stronger," Manuel said.
His teammates are enjoying his improvement.
"It's been good that somebody has been able to step up and fill the role of having to drive in runs," winning pitcher Vance Worley said of Ruiz. "I think it's just a matter of time before a lot of other guys are doing it."
This was a San Diego team that has the fewest wins in the National League, 11, but these days the Phillies can't take anything for granted. In fact, they split a four-game series last month in San Diego.
To demonstrate the Padres' lack of punch, Alonso was their cleanup hitter against the Phillies and he entered the game with zero home runs.
That changed in the sixth when he crushed a 2-2 fastball off Worley that hit off the Budweiser sign in front of the second deck in right field. Alonso battled back after being down in the count 0-2 to cut the Phillies lead to 4-3.
That was only San Diego's 13th home run of the season, the lowest total in the majors. The Padres still trail Texas' Josh Hamilton, who entered the weekend with 15 home runs.
The Phillies responded in the sixth when Freddy Galvis stroked an RBI double off starting pitcher Clayton Richard. Despite his struggles at the plate it was Galvis' 12th RBI, which is fourth on the team.
Worley (3-2) went six innings, allowing six hits and three runs, all earned. He struck out nine and walked two.
Antonio Bastardo followed with two hitless innings, striking out three and Chad Qualls pitched a scoreless ninth as the bullpen that struggled mightily in a three-game sweep with the New York Mets, enjoyed a strong night.
Contact Marc Narducci at 856,779-3225, firstname.lastname@example.org or @sjnard on Twitter.