The Yankees have lost seven of their past eight games and are 2-7 in August, with the skid putting their top seed hopes in the American League in jeopardy.
Sam Haggerty had blasted the Mariners into a 1-0 lead with a solo home run in the sixth inning.
After Tuesday's 1-0 extras' loss to the Mariners, the Yankees actually went scoreless across 19 innings, breaking that run in the seventh inning on Wednesday.
But the Mariners, who won the season series against the Yankees for the first time since 2002, fought back through Santana, with his two-run blast being his 11th homer of the season.
Mariners pitcher Robbie Ray played his part, striking out seven batters as well as Seattle moved to 61-52, while the Yankees are 71-41.
Dodgers clinch 10 straight wins
Joey Gallo blasted a three-run homer to help the Los Angeles Dodgers secure their 10th win in a row with an 8-5 triumph over the Minnesota Twins.
The Dodgers were trailing 4-2 in the fifth inning but rallied back with Chris Taylor homering the go-ahead run. Gallo, who was traded to the Dodgers from the Yankees last month, came up with his 13th home run of the season in the seventh inning.
The 10-game win streak is the Dodgers' longest since they won 11 in a row in July 2017, while they swept the four-game series against the Twins with a 32-10 run record.
Lindor stars as Mets winning run continues
The shortstop helped the Mets clinch a series sweep with a second-inning two-run single, opening up a 4-0 lead and making franchise history.
Lindor, who finished with three runs, two hits and two RBIs, moved to 81 RBIs for the season, tying with Jose Reyes in 2006 for a Mets' single-season record.