On December 12, 2014, Santana signed with the Minnesota Twins on a four-year, $54 million deal with an option for a fifth year. On April 3, MLB announced that Santana would be suspended for 80 games after testing positive for Stanozolol, a performance-enhancing drug. On July 5, 2015, Santana was activated from his 80-game suspension and made his season debut against his former team, the Kansas City Royals. After finishing with a 7–5 record and a 4.00 ERA in 2015, Santana served as the ace of the Twins rotation during a disappointing 2016 season for the team. Despite a 7–11 record, largely due to poor run support, Santana finished with a strong 3.38 ERA in 181 innings pitched (30 starts).