Wedge managed the Mariners for the first time since he had a mild stroke a month ago. He acknowledged being anxious about getting back on the bench and called his ailment "a heads up."
Garrett Richards (4-5) allowed four hits in 7 1-3 innings and two relievers finished the five-hitter for Los Angeles.
Nelson snapped an 0-for-17 slide when he connected in the second for his third homer. Josh Hamilton scored on Nelson's long ball after leading off the inning with a single, and it was the only time Hernandez (12-7) was touched all night.
The biggest problem for Hernandez was the gem Richards was tossing on the other side.
Richards (4-5) struck out four and walked two, but was forced out of the game after taking a liner off his right forearm. The right-hander had thrown just 89 pitches and was in line for a career performance before leaving.
Dustin Ackley led off the eighth with a shot back to the mound that caught Richards and deflected to shortstop Erick Aybar, who threw to first for the out. Manager Mike Scioscia immediately went to the mound and Richards was replaced by Dane De La Rosa.
The Angels said Richards had a forearm contusion. De La Rosa finished off the eighth and Ernesto Frieri pitched the ninth for his 27th save.
Wedge's month off was filled with doctor's appointments and meetings, researching and relaxing, with the goal of figuring out why he had suffered a stroke at 45 years old and how to prevent it from happening again.
"It's a shot across the bow, it's a mulligan, it's a heads up," Wedge said before the game. "And I'm taking it as such."
Hernandez was handed consecutive losses for the third time this season, even though he was cruising in his final innings. But a taxing fourth inning where he had to throw 29 pitches and left runners stranded on the corners ended up equaling an early exit. Hernandez struck out Grant Green to end the threat in the fourth, and then struck out four of the final six batters he faced. He recorded 10 strikeouts for the 25th time in his career and the fourth time this season.
Seattle finally got multiple runners on base in the same inning when Brad Miller led off the sixth with a single and Kyle Seager walked on a 3-2 pitch with one out. Richards quickly defused the threat, getting Kendrys Morales to ground into a double play. He also got Endy Chavez to ground into a double play to end the seventh after Justin Smoak singled.