Santana (1-3) gave up six runs on nine hits in 3.2 innings of work.
Lorenzo Cain was 4-for-5 with a double and two RBIs, while Salvador Perez continued to feast on Twins pitching. After five hits in the series opener on Friday night, he was 2-for-4 with a home run for an encore.
Eduardo Escobar was 3-for-4 with a double and an RBI.
The Twins will send Tyler Duffey (1-3) to the mound in the series finale on Wednesday against Dylan Gee (1-1).