A star high school player, Freese declined a college baseball scholarship from the University of Missouri, a Division I NCAA baseball program in the Big 12 Conference. Needing a break from baseball, he sat out his freshman year of college before feeling a renewed urge to play the game. He transferred to St. Louis Community College-Meramec, a junior college, where he played for one season before transferring to the University of South Alabama.

The San Diego Padres drafted Freese out of South Alabama in the ninth round of the 2006 Major League Baseball Draft. Before the 2008 season, the St. Louis Cardinals acquired Freese for Jim Edmonds. He made his MLB debut on Opening Day 2009 but his breakout season came in 2011. For the Cardinals, Freese batted .545 with 12 hits in the 2011 National League Championship Series, and set a MLB postseason record with 21 runs batted in, earning the NLCS MVP Award, World Series MVP Award, and the Babe Ruth Award, naming him the MVP of the MLB postseason.