Detroit had lost 10 straight to the Angels and hadn't beaten them since Aug. 26, 2012. The Tigers snapped that skid behind a sharp outing by Scherzer and home runs from Nick Castellanos and Victor Martinez.
Albert Pujols hit his 498th homer, connecting for a solo shot in the ninth.
Scherzer (1-1) allowed a run and three hits with two walks. The AL Cy Young Award winner earned his first victory of the season, striking out Mike Trout three times and Pujols twice.
C.J. Wilson (2-2) gave up three earned runs in five innings.
J.B. Shuck led off the game with a homer, but that was all the scoring for the Angels until Pujols homered for the second straight day, hitting his sixth shot of the season.
The Angels had 10 extra-base hits in an 11-6 win over the Tigers on Friday night, and Shuck snapped his 0-for-14 slide with a drive to right to start the first inning Saturday.
But in a sign of things to come, Scherzer struck out Trout, Pujols and Raul Ibanez immediately after allowing the homer.
Wilson made it through a shaky first inning, but Castellanos hit a two-run homer in the second to put the Tigers ahead to stay.
Detroit added an unearned run in the third. Miguel Cabrera reached on an error by right fielder Brennan Boesch and went to second on a wild pitch. Cabrera was then called out at third when Trout - his foil from the last two American League MVP races - made a nice throw from center. The Tigers challenged the call, however, and Cabrera was ruled safe.
Cabrera scored on a sacrifice fly by Austin Jackson to make it 3-1.
Martinez added a solo homer in the fifth, and Ian Kinsler's sacrifice fly in the eighth made it 5-1.
Scherzer, meanwhile, looked every bit his Cy Young self. Trout, Pujols and Ibanez - the second, third and fourth hitters in the Los Angeles lineup - went 0 for 8 with seven strikeouts and a walk against the Detroit starter.
NOTES: The Angels have outscored opponents 19-5 in the first inning this year. ... Los Angeles entered the game with a major league-high 27 homers and an AL-worst 20 homers allowed - then added to both those totals. ... Detroit RHP Rick Porcello (1-1) faces Angels LHP Hector Santiago (0-2) on Sunday.