Miami looks to snap a five-game losing streak to the surging Mets on Friday night when it faces Santana, who has dominated the Marlins throughout his career.
Miami (16-15) went 8-1 on a trip that ended a 5-3, 12-inning victory over Houston on Wednesday. Omar Infante drove in two runs on a bases-loaded single in the 12th after Steve Cishek blew the save in the ninth.
"We got the win, that's all that matters," starter Josh Johnson told the Marlins' official website after going seven innings. "It was an unbelievable road trip. ... Maybe we can go back home and start something there and keep winning ball games."
Despite the outstanding road swing, the closer problem follows the Marlins home, though Heath Bell pitched a scoreless 10th inning Wednesday. Bell was demoted from the spot after blowing four saves in seven chances.
"I want to see him throw the ball the way he did today with confidence," manager Ozzie Guillen said. "I believe we're a better ball club with him as a closer."
Miami, 6-5 at home, could see its momentum come to a quick halt if it can't change its fortunes against Santana and the Mets (18-13).
Santana (1-2, 2.61 ERA) has posted a 1.83 ERA in his last three starts - all Mets wins - and is coming off his first victory since Sept. 2, 2010, before shoulder surgery kept him out last season. He's been even more effective against the Marlins in his career, going 6-1 with a 1.46 ERA in 10 starts, including an 0.84 ERA in the last six.
The left-hander faced the Marlins for the first time in nearly two years April 24, giving up one run and striking out 11 in 6 2-3 innings of a 2-1 home victory.
Santana finally got his long-awaited win Saturday, allowing three runs in seven innings to beat Arizona 4-3.
''He's been throwing the ball really well - probably should have had a couple of wins already by now,'' catcher Mike Nickeas said.
Santana will be opposed by fellow left-hander Mark Buehrle (2-4, 2.83), who's coming off a superb outing that followed his shortest start of the season.
Buehrle threw a five-hitter to defeat San Diego 4-1 on Saturday, bouncing back from a five-inning stint in which he gave up seven runs - four earned - in a 9-5 loss to the Diamondbacks on April 30.
He pitched well in his first career start against the Mets, giving up two runs on a David Wright homer in seven innings April 25, but suffered a 5-1 loss.
"It starts with starting pitching," Buehrle told the Marlins' official website. "We've got to come out and throw zeros to give the offense a chance to get going. When we were playing them (in April), we weren't playing well. Hopefully things will turn."
The Mets swept that three-game series to extend their run in the series to five, and surprising New York brings an overall five-game winning streak into Friday after beating Philadelphia 10-6 on Wednesday.
The Mets overcame a 4-2 deficit, scoring three times in the seventh before Ike Davis hit a three-run homer in the eighth. New York is five games above .500 for the first time since July 19, 2010.
The Mets rallied in the seventh inning or later in all three contests against the Phillies.
"We're playing pretty good baseball right now and getting good results," shortstop Justin Turner said.
The Mets' last six-game winning streak was April 21-27, 2011.