The opposite-field shot to right-center was the first home run by a pitcher in Mariners history, and the first slam by an AL hurler since Cleveland's Steve Dunning went deep against Oakland's Diego Segui on May 11, 1971, according to the Elias Sports Bureau.
Three innings later, Hernandez sprained his left ankle while covering home plate on a run-scoring wild pitch. Carlos Beltran slid hard into the feet of Hernandez, who left the game one out short of being eligible for a win. After trying a painful warmup pitch, he had to be helped to the dugout by team trainers.
Roy Corcoran relieved Hernandez and worked 1 1-3 hitless innings. Ryan Rowland-Smith (2-1) struck out three in two perfect innings, and Arthur Rhodes earned his first save since 2006 with Philadelphia.
Beltran's RBI single off Sean Green cut it to 5-2 in the ninth before Rhodes fanned Carlos Delgado and Damion Easley with two on.
Jose Lopez added a run-scoring single for the Mariners, who improved to 12-25 on the road and 2-2 since new manager Jim Riggleman replaced the fired John McLaren.
The Mets fell to 3-3 under interim skipper Jerry Manuel, who managed his first game at Shea Stadium since taking over when Willie Randolph was fired last week.
Santana (7-6) allowed five runs - one earned - and seven hits in seven innings. It was his third loss in 16 starts with New York when giving up one earned run.
The Mets have dropped his last four outings, and the two-time Cy Young Award winner is 0-3 during that span.
Just before Hernandez homered, an error by third baseman David Wright extended the second inning.
The 6-foot-3, 230-pound Hernandez took a healthy hack at the first pitch he saw from Santana and clapped his hands while rounding first base. The home run came in his first plate appearance of the season and made him 2-for-9 with five RBIs and six strikeouts in his major league career.
His next time up, Hernandez dropped down a successful sacrifice bunt.
Hernandez threw 34 of his 51 pitches for strikes in 4 2-3 innings. The 22-year-old right-hander, who entered 4-0 with a 0.95 ERA in his previous four starts, allowed one run and two hits.
The last National League pitcher to hit a grand slam also did it at Shea Stadium. Dontrelle Willis, then with Florida, accomplished the feat against the Mets on July 7, 2006.
