League, who lost two extra-inning games in Baltimore in the previous series, gave up a two-run home run to Travis Hafner with two outs after inheriting a 4-2 lead.
League surrendered back-to-back doubles to Michael Brantley and Asdrubal Cabrera to lead off the bottom of the ninth, cutting the lead to 4-3. Cabrera's hit carried over the head of rookie left fielder Carlos Peguero, who didn't get back on the ball as it sailed to the warning track.
Cabrera advanced to third on a groundout by Shin-Soo Choo, but League got Carlos Santana to ground to second against a drawn-in infield before Hafner ended it with a blast to center field.
Youngsters Carlos Peguero and Justin Smoak had put the Mariners in position to win with home runs earlier in the game, giving Fister some welcome run support.
But after Fister held Cleveland in check on four hits over eight stout innings, League took yet another loss as Seattle suffered its sixth straight setback.
It all spoiled a homecoming to Cleveland for Mariners manager Eric Wedge, making his first return to the city where he led the Indians from 2003-09.
The Mariners had hit just three home runs over the previous 12 games, but unloaded twice at Progressive Field on a night they managed just four other hits.
Smoak's two-run blast to right-center field in the seventh inning lifted the Mariners into a 3-2 lead after they'd been handcuffed all night by Cleveland starter Fausto Carmona.
In the first six innings, the only hit Seattle managed against Carmona was Peguero's first Major League home run -- a towering 422-footer to right field on a first-pitch changeup.
Peguero, making his third start since being called up to replace Milton Bradley, cut Cleveland's lead to 2-1 with his no-doubter.
The Mariners weren't able to do much else with Carmona, a 2010 All-Star who lost twice to Seattle last year despite allowing just three runs in 14 innings.
The 27-year-old Dominican was stingy again Friday, until the Mariners pushed across three runs in the seventh on four hits. Smoak's home run came after a leadoff single by Chone Figgins. Jack Cust followed Smoak with a double, then scored on a single deep in the hole at short by Brendan Ryan.
Carmona eventually gave way after 7 2/3 innings, giving up six hits and four runs.
Fister, who gave up 14 hits in 5 2/3 innings in his previous start against the White Sox, was an early victim of the long ball as Shin-Soo Choo homered in the first and Michael Brantley followed suit in the third.
Fister had given up just one home run in his previous seven starts this season. But the lanky right-hander settled in after Brantley drove his shot off the top of the wall in right field, retiring the next 11 batters and once again giving the Mariners a chance.
Fister finished with four hits over eight innings in an impressive outing that lowered his ERA to 3.22 as he remained 2-4. The Mariners had scored just three runs in Fister's four losses this season.
(Courtesy of: www.mariners.com)