He recorded just one at-bat on the afternoon and used it to make Seattle pay.
Encarnacion hit a tiebreaking solo shot in the sixth inning that helped Toronto to a 7-2 victory. It was his third home run in as many days and 15th extra-base hit of the season.
"I was looking for that pitch, looking for the change-up," Encarnacion said. "When he threw me the change, I made a good swing on it."
Encarnacion also had two walks and was hit by a pitch in Toronto's five-run eighth inning. Canadian Brett Lawrie drove in two runs and Jeff Mathis added a two-run homer to help Henderson Alvarez (1-2) record his first win of the season.
"I thought he did well," Mathis said of Alvarez. "He threw his sinker and kept it down in the zone. He got a lot of early outs and ground ball outs and I think that was the key to his success today."
Encarnacion, who hit a grand slam a day earlier, lined a 1-1 pitch from Jason Vargas (3-2) over the wall in left-centre field for his seventh homer of the season.
Alvarez allowed six hits and a career-high three walks as Toronto (12-10) won the rubber match of the three-game series. He gave up one earned run and picked up his first victory in 10 starts dating back to last season.
"He kept his composure and didn't really build an inning by pitching out of the strike zone or issuing a walk in combination with a base hit," said Jays manager John Farrell. "So he's been very consistent for us."
Vargas allowed four hits and two earned runs over six innings for Seattle (11-12).
Chone Figgins opened the game with his ninth career leadoff home run. He hit a 1-2 pitch to right field that barely made it over the wall.
Dustin Ackley followed with a double but Alvarez settled down to get the next three outs.
In the fourth inning, Jose Bautista got a second chance when Mariners catcher Miguel Olivo missed a popup in foul territory about halfway down the third-base line. Bautista couldn't take advantage and hit another popup, which was caught by shortstop Munenori Kawasaki.
Encarnacion followed with a walk and Eric Thames picked up Toronto's first hit with a flare that fell in front of Figgins in left field. Encarnacion advanced to third and Thames hustled in to second base on the play but they were left stranded when Lawrie flew out to Figgins.
The Blue Jays tied the game in the fifth inning. Colby Rasmus singled, moved to second on a Yunel Escobar grounder and scored on Kelly Johnson's single to right field.
Figgins made a great catch on a Bautista flyout to end the inning, fighting off the outstretched arms of fans in the front row to come up with the ball. A frustrated Bautista — who is hitting just .190 on the season — slammed his helmet to the turf in frustration after rounding first base.
Seattle threatened in the sixth with runners on first and second with one out. Alvarez responded by striking out Olivo and getting John Jaso to fly out.
Alvarez was relieved by Evan Crawford in the seventh after allowing a leadoff single to Kawasaki, who moved to second on a sacrifice bunt and to third on a ground ball. Crawford got the dangerous Ichiro Suzuki to ground out for the final out of the inning.
Bautista singled in the eighth inning and moved to second when Encarnacion was hit by a pitch. The Jays executed a double steal and Rajai Davis was intentionally walked with one out and a base open.
That set the stage for Lawrie, who slashed a single to right field to score two runs. Olivo later tried to pick Davis off third but the throw was off-line and the speedy outfielder ran home.
After a Rasmus strikeout, Mathis hit his second homer of the season into the second deck in left-centre field.
Francisco Cordero gave up a solo homer to Olivo and a double to Jaso in the ninth inning.
Notes: Bautista went 1-for-4 on the day. ... Lawrie, from Langley, B.C., has a nine-game hitting streak on the go. He has recorded a hit in 15 of his last 16 games. ... The Blue Jays will cap the six-game homestand with a three-game series against the Texas Rangers. Kyle Drabek (2-1) will get the start for Toronto in Monday's series opener against Japanese right-hander Yu Darvish (3-0). ... The game took two hours 36 minutes to play. ... Davis left the game in the eighth inning. Farrell said Davis is day-to-day with a right wrist contusion and will be re-evaluated Monday. ... Attendance was 22,320.