Carlos Santana belted a two-run homer in the first inning while Justin Sellers and Nyjer Morgan each finished with two hits, a run scored and an RBI for the Indians.
Cleveland starter Corey Kluber and his counterpart, Tyson Ross, each gave up three runs during their outings.
Xavier Nady and Rymer Liriano both homered for the Padres.
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Goodyear, Ariz. -- Luke Carlin hit a three-run double during Cleveland's seven-run eighth inning as the Indians pounded out 16 hits in a 12-7 win over the San Diego Padres.