Trumbo's clout in the fifth inning extended a 3-0 Angels lead. Albert Pujols added two hits, including an RBI single, as Los Angeles clinched its three-game series.
Santana (7-10) limited the Red Sox to two runs on five hits, walking a pair and fanning four.
Boston starter Aaron Cook (3-7) was roughed up for 11 hits over five innings, yielding five runs (four earned).
Jarrod Saltalamacchia bashed a two-run homer for the Red Sox.