Santana (6-10), who had lost his last seven home starts against the Indians, walked one and struck out four.
Chris Iannetta homered and drove in two runs for the Angels, who got two RBI from Vernon Wells. Kendrys Morales had three hits and scored twice for LA, which has won two straight following a three-game losing streak.
Cleveland starter Roberto Hernandez (0-1), whose used to pitch under the name Fausto Carmona, started and went six innings, allowing eight runs on 10 hits, with no walks or strikeouts.
The Indians have lost two straight and three of their last four.
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