Mauer, who led Minnesota's 12-hit attack in Monday's victory over the Angels, sparked a 15-hit assault Tuesday, extending his nine-game hitting streak as the Twins clinched their three-game home series.
Brian Dozier contributed two hits with two RBI while Wilkin Ramirez and Justin Morneau each provided a pair of hits and drove in a run for Minnesota.
Mike Pelfrey (2-1) overcame a rough start to earn the decision, allowing four runs on seven hits over five innings.
Glen Perkins survived a hit and walk in the ninth to record his third save.
Angels starter Jason Vargas (0-2) was pounded for five runs on nine hits over 3 1/3 frames as Los Angeles fell to 4-10 to start the season.
Mike Trout went 2-for-4 with three RBI in the loss.