Napoli's 16th home run came on a 3-1 cutter from Mariners reliever Miguel Batista with two outs and pinch-runner Chone Figgins on first base much to the delight of the crowd of 43,743 at Angel Stadium.
"It's a great feeling," said Napoli, who helped the Angels to their eighth walk-off win of the season. "I've never done it before. To see the guys cheering and to able to do that was a great feeling."
Napoli's approach wasn't to hit a home run but to drive the ball with the chance to score the fleet-footed Figgins, who entered the game as a pinch-runner for Robb Quinlan, who drew a two-out walk.
"I was trying to get a pitch I could hit in the gap with Figgy on first base because he can fly," Napoli said.
But instead it was the ball that flew over the left-field fence instead of Figgins flying around the bases.
The at-bat capped Napoli's great game at the plate, where he drove in a game-high four runs.
But in Angels manager Mike Scioscia's eyes, it was an at-bat in which Napoli didn't get a hit that was even more impressive.
Napoli's sacrifice fly on an 0-2 count from Roy Corcoran in the seventh inning is what impressed Scioscia the most. The fly ball hit to center field was just deep enough to score Juan Rivera from third base and tied the game at 3.
"I really liked the sacrifice fly," Scioscia said. "It was a tough pitch and a contact situation so you really have to put that ball in play. He really shortened his swing and got the ball into center field."
Napoli's sacrifice fly and home run helped the Angels to their 38th come-from-behind win of the year and bailed out left-hander Joe Saunders, who, despite pitching well, left the game after seven innings with his team trailing by a run.
Saunders turned in his third impressive start in a row after two lackluster starts in August and looks like he is returning to his early-season form that earned him a trip to New York for the All-Star Game.
"I think Joe found something with his rhythm a couple of starts ago and is ... more in line from what we saw early in the season," Scioscia said. "His last couple of outings have been really solid and hopefully he'll keep it moving it from here."
Saunders, who already set a career high in wins this season with 15, made his first All-Star appearance and saw the birth of his first child in early July, called the season "a whirlwind but in a good way."
Friday's start wasn't quite a whirlwind, however, as he accomplished his goal of keeping his team in the game.
"Tonight was one of those games where you don't have your best stuff or your worst stuff," Saunders said. "But what makes a good pitcher, I've been told over my career, is that you can battle through those starts and give your team a chance to win."
Saunders was saddled with the no-decision as Jose Arredondo earned his eighth win of the season after pitching a perfect ninth inning.
The Mariners opened the scoring in the first inning on Adrian Beltre's run-scoring double that extended his hitting streak to 15 games. And they took the lead again in the fifth inning on RBI singles by Raul Ibanez and Beltre off Saunders.
The Angels scored their first two runs in the second inning on a run-scoring triple by Quinlan, who then scored on a bloop broken-bat single by Napoli. It was the first hit of what would become a perfect 2-for-2 day at the plate for the catcher.
"I had a good night swinging the bat," Napoli said. "What else could you ask for?"
It was the Angels' fifth win in six games and they've now won both games since clinching the AL West title on Wednesday to prove that they aren't taking it easy down the stretch.
"We're coming out here to win every day," Napoli said. "Just because we clinched it doesn't mean we're going to lie down."