The Blue Jays battered Hernandez (11-5) and knocked him out after just five innings, matching his shortest start of the season.
A leading contender for a second AL Cy Young Award, Hernandez got no help from his defense that committed three errors that led to three unearned runs while he was on the mound.
Despite lasting just five innings, Hernandez's ERA only rose from 2.30 to 2.39. Hernandez had not lost since May 25, a span of 12 starts.
Toronto's Josh Johnson (2-8) pitched well with his potential spot in the rotation at stake. Johnson threw five scoreless innings and won for the first time since June 23, snapping a six-game losing streak.
Reyes brought the huge contingent of Blue Jays' fans to their feet from the start. He lined Hernandez's first fastball of the night 399 feet into the seats in right for his eighth homer of the season. It was Reyes' 18th career leadoff homer and first this season.
For Hernandez, it was just the second leadoff homer allowed in his career and a precursor to a tough night.
Toronto scored three times in the fourth helped by two Seattle errors. Emilio Bonifacio had the big hit with a two-out double into the gap in right-center field.
Bonifacio's hit came after three defensive breakdowns by Seattle: Kyle Seager committed his second error of the night, shortstop Brad Miller threw wildly to second trying to start a double play and Miller failed to hold the ball when tagging Brett Lawrie on a stolen base.
Reyes followed Bonifacio with an RBI single to cap the big inning. Toronto then scored twice more in the fifth when Colby Rasmus dropped an RBI single on a two-out, 0-2 pitch from Hernandez. That was followed by Lawrie's RBI single and a 6-0 lead.
Seattle's ugly night defensively was capped in the seventh when Raul Ibanez committed the Mariners' fourth error spiking an attempted throw from left field into the ground just a few feet in front of him and allowing Jose Bautista to score Toronto's seventh run.
Toronto's offensive output made it an easy night for Johnson, who in his previous four starts had an ERA of 14.06, but was masterful against the Mariners.
It was the second time this season Johnson didn't allow a run and a key for him was getting out of the first when Seattle had runners on the corners and one out. Johnson got Kendrys Morales to ground into a double play and Seattle never got a runner to third base until the seventh on Miller's two-run triple.
Notes: Rasmus made a highlight catch robbing Morales of a potential home run in the sixth inning pulling in a deep drive to center field. ... Seattle optioned closer Tom Wilhelmsen to Triple-A Tacoma on Tuesday in the hopes he can rediscover the command of his fastball. Seattle recalled reliever Carter Capps to take Wilhelmsen's spot. Seattle also released OF Jason Bay, who was designated for assignment on July 29. ... Texas' Ian Kinsler is the only other batter to hit a leadoff homer off Hernandez. ... The four errors by Seattle were its most since committing six vs. the Angels in September 2011.