The normally wild Deduno (5-2) struck out a career-high nine with no walks to help the Twins snap a seven-game losing streak against Seattle and win for just the fourth time in their last 20 games overall.
After Trayvon Robinson singled with one out in the first inning, Deduno retired the next 18 hitters, all but one on groundballs or strikeouts.
Kyle Seager singled up the middle to break the streak in the seventh, but Deduno got John Jaso to ground out and fanned Justin Smoak on a curveball in the dirt to end the inning.
Plouffe gave the Twins a 5-0 lead in the fourth with his 20th home run and first since returning Aug. 13 after missing 21 games with a sore thumb.
Josh Willingham hit a 432-foot shot into the second deck in left field an inning later, his 32nd of the season.
Before Wednesday's longballs, the Twins had just one home run in their last 11 games.
After Jason Vargas (13-9) walked the first two hitters to start the third, Joe Mauer notched the first of his three hits and made it 2-0.
It didn't get any better for Vargas as Justin Morneau drove in a run later in the fourth before Plouffe and Willingham went deep.
Vargas failed to finish five innings for his second straight start. He allowed six runs on eight hits over 4 2-3 innings, making him 0-2 with an 11.42 ERA in his last two outings.
The loss was just Seattle's fourth in its last 14 games and snapped a 16-game winning streak against teams under .500.
Deduno entered the game with a 37-to-30 walk-to-strikeout ratio, but didn't walk anyone for the first time all season.
Seattle's hitters flailed at the lanky right-handers curveballs in the dirt and couldn't figure out how to elevate Deduno's darting fastball.
After winning his first four decisions, Deduno had lost his last two, including an ugly outing in Texas last week where he allowed 11 hits and seven runs in five innings.
After managing just two runs and nine hits through the first two games of this series, Minnesota broke out with 16 hits and its highest run total since scoring nine against Detroit on Aug. 13.
Seattle was marching back to the .500 mark before being cooled by Deduno. It was the first time the Mariners have been shut out since July 15 at Texas.
NOTES: Twins LHP Scott Diamond dropped his appeal of a six-game suspension for throwing behind Josh Hamilton and being ejected in a game against the Rangers last week. Minnesota announced Diamond's decision one day after he allowed five runs in seven innings of a loss to Seattle. ... Mariners manager Eric Wedge said OF Michael Saunders likely will return from a growing strain on Thursday after missing five games. ... An MRI on Denard Span's sore collarbone area showed that the Twins' outfielder has a sprained SC joint. Span was originally hurt on Aug. 12 and has only played four games since. "I guess we're going to take it kind of day to day. It's going to be painful, and it's going to be based on how I feel," Span said. "There will be days I can go out there and swing and there will be bad days." ... Minnesota recalled 1B Chris Parmelee from Triple-A Rochester and outrighted RHP Jeff Gray to Rochester. ... Seattle's Blake Beavan faces Brian Duensing in Thursday's series finale.