"It gave us a big lift," said manager Mike Scioscia. "The kids came up and just played terrific ball."
Vladimir Guerrero and Casey Kotchman also homered and Howie Kendrick, who was only called up from Salt Lake on April 24, added a RBI single.
Napoli is the 92nd player and third in Angels' history to homer in his first big league at-bat. The two previous Angels were Don Rose in 1972 and Dave Machemer in 1978.
"I couldn't ask for anything more," said Napoli. "Down 1-2 [count], happened to hit a curve ball."
He added he was looking for a curve because Detroit starter Justin Verlander (3-3) had set up Kendrick with fastballs and then struck him out with a curve. But Verlander's curve to Napoli wasn't nearly good enough.
"I gave him his 'Welcome to the Majors' moment with a breaking ball that was nice and pretty on the tee," Verlander said.
Angels' starter Kevin Gregg (2-0) got the win. He allowed a run and three hits in seven innings. He didn't walk a batter and struck out three.
"I just wanted to come out and challenge them really," said Gregg. "And not fall behind in the count."
Verlander gave up four runs, three earned, and nine hits in six innings.
Magglio Ordonez's sacrifice fly tied it 1-1 in the fourth for the Tigers. But the Angels took a 3-1 lead in the fifth on Kotchman's first home run of the season, leading off the inning, and Murphy's first Major League hit -- which produced a run.
Murphy flew all night from Salt Lake City, and arrived at Detroit Metropolitan Airport at about 10:40 on Thursday. He came straight to Comerica Park.
Kendrick made it 4-1 with his RBI single in the sixth. Guerrero added a three-run homer in the seventh.
Curtis Granderson hit a sacrifice fly for the Tigers in the eighth.
"It's good to see the kids come up and perform like they did today," said Scioscia. "It indicates that our player development is working."