Edinson Volquez earned the victory, giving up only two runs on seven hits with one walk and eight strikeouts in six strong innings.
The right-hander's first quality start on the road since May 28 was bolstered by a Padres lineup that made Marlins starter Ricky Nolasco work.
After falling behind, 1-0, through one, the Padres began chipping away at Nolasco.
"We drove his pitch count up early," Padres manager Bud Black said. "After three innings, I believe he was over 60 pitches. So, he was stressed and working hard. That takes its toll on a pitcher for sure."
A Will Venable RBI single tied the game in a 27-pitch second inning for Nolasco, and Forsythe put San Diego ahead for good with a two-run shot in a third inning that required 23 pitches from Miami's right-hander.
"Luckily, I got a couple of balls up, and I didn't miss them," Forsythe said.
Forsythe and Venable paced the Padres' offense. The former reached base four times in five plate appearances, and Venable tallied a game-high three RBIs.
They were two of five San Diego batters with multi-hit performances.
"We stringed together some good at-bats," Venable said. "We put the pressure on those guys and just kept it coming with the good [at-bats] and found some holes and just a good, all-around game for us."
Five Padres posted at-bats of six or more pitches in the first three innings. Even a 1-2-3 fourth took Nolasco 18 pitches.
By the time Nolasco reached the sixth, he had thrown 96 pitches, and the Padres quickly took advantage and added insurance to their 3-2 lead.
Chase Headley led off with a single, Kyle Blanks smacked a double and both runners came home on back-to-back RBI singles by Yasmani Grandal and Venable to put San Diego up, 5-2.
The Padres chased Nolasco from the game at 110 pitches with no outs in the sixth. His five-plus frames marked his shortest outing since May 14.
"It was just a struggle today," Nolasco said. "I thought I was going to be able to turn the corner there. They just kind of got me. I couldn't put guys away. I just kind of buried the team right there."
Venable added: "We just beat him and took advantage at the end and knocked him out of there."
San Diego put a runner on base against Nolasco in every inning but the fourth.
"He has a good breaking ball," Black said. "He's got a good running fastball. The mistakes that he did make, we did some damage."
Even when Nolasco left the game, the Padres' lineup kept working.
San Diego plated three more runs in the seventh and the eighth, capping their highest-scoring game since a 10-9 loss to the Rockies on June 7.
"We had some good at-bats," Black said.
While the Padres did the most damage on the scoreboard, the Marlins scored the game's first run.
Logan Morrison followed a two-out single by Giancarlo Stanton in the first inning with a run-scoring triple to right-center.
Two innings later, with Miami trailing, 3-1, Stanton again provided an offensive spark. Placido Polanco drew the lone walk by Volquez and scored on a double by Stanton to right-center.
Volquez allowed a baserunner in every inning he pitched, but the right-hander stood strong against a Marlins lineup that stranded nine men on base.
"They got their hits, but he was able to slow them down," Black said. "When they did stress him a little bit with base runners, he made pitches."
Black was happy that Volquez kept walks to a minimum Friday after issuing seven free passes in his most recent outing -- a 6-1 loss to the Dodgers on June 22.
"He was repeating his delivery." Black said. "The only time I really thought that he came out of his delivery was when he tried to throw a fastball away to Polanco and threw it in the dirt. But after that, I thought a repeatable delivery was the key to that."
The Padres' victory Friday night helps them start their 10-game road trip on a high note. This marks their longest stretch away this season.
"It's huge, especially with a 10-day road trip," Forsythe said. "When you get that first one out of the way, it's nice -- a good confidence booster. You've got to ride it out for as long as you can."