The homer, Napoli's 20th of the season, drew the Angels within 2-1 leading off the top of the third.
Bobby Abreu, Torii Hunter and Kendry Morales each drove in a run, one run scored on Craig Breslow's sixth-inning balk, and Erick Aybar had three hits for the AL West champion Angels, who carry a three-game sweep into the AL Division Series against Boston Thursday.
The winner was starter Joe Saunders (16-7).
Kevin Jepsen earned his first save despite giving up a run and two hits in the ninth.
Oakland's Eric Patterson and Cliff Pennington had two hits and one RBI apiece. Matt Carson had a hit and a sacrifice fly, while Nomar Garciaparra added two hits for the Athletics (75-87), who finished last in the AL West.
The losing pitcher was Jeff Gray (0-1).