Sizemore was drafted by the Tigers in the fifth round of the 2006 Major League Baseball Draft out of Virginia Commonwealth University. In 2009, Sizemore was rated Detroit's 7th best prospect by Baseball America. On October 23, 2009, Sizemore broke his left leg during a collision while playing in the Arizona Fall League the previous day. On October 27, 2009, Sizemore had surgery on his fractured left ankle including screws being place to stabilize his ankle joint. He was able to return to action in time for Spring Training in 2010. Although Sizemore has not been known as a Major League shortstop, he has, according to his baseball card from 2007 Bowman Heritage Signs of Greatness, played that position while in the minor leagues. On April 9, 2010, Sizemore got his first major league hit against the Cleveland Indians. Detroit won the game 5–2. On April 11, 2010, Sizemore got his first extra base hit and an RBI in the bottom of the Seventh at Comerica Park against the Cleveland Indians. Jensen Lewis was pitching. Sizemore hit his first major league home run off Los Angeles Angels pitcher Joel Piñeiro on April 30, 2010. Coming in the same inning as Brennan Boesch's first career home run, it was the first time two Tigers had hit their first career home runs in the same inning since Pop Dillon and Kid Elberfeld did it in 1901. Detroit optioned Sizemore back to the Triple-A Toledo Mud Hens on May 16, 2010. Sizemore's average had slumped to.206 and he was in the midst of an 0–14 streak. Detroit recalled newcomer Danny Worth from Toledo and transferred veteran Carlos Guillén to second base. Sizemore was called up again on July 21 to play third base in place of the injured Brandon Inge. On May 3, 2011 Sizemore was called up again to the 25 man roster, replacing second baseman Will Rhymes. In his first game back, Sizemore faced the Yankees and went 3 for 4 with a double and an RBI. The 4–2 win for the Tigers also snapped a seven-game slide.
Oakland Athletics
On May 27, 2011, Sizemore was traded to the Oakland Athletics for David Purcey. On June 6, 2011, Sizemore was called up by the A's. While he debuted in the majors as a second baseman, he converted to play third base for the A's, who sent Kevin Kouzmanoff to Triple-A. Sizemore finished the 2011 season with the Athletics, batting.249 over 93 games with 11 home runs and 52 RBIs. On February 27, 2012, it was announced that Sizemore tore his ACL in his left knee, causing him to miss the entire 2012 season. On April 10, 2013, it was announced that Sizemore re-tore his ACL in his left knee, causing him to miss the rest of the 2013 season. Sizemore was placed on the 60-day disabled list on April 22 to make room for Casper Wells. He elected free agency on November 20, 2013.
On January 2, 2015, he signed a minor league deal with the Miami Marlins and was assigned to AAA. He was released on July 13 after posting just a.223 batting average at AAA.
Sizemore signed a minor league deal with the Washington Nationals in August 2015. On November 20, he re-signed with the Nationals organization. Sizemore was released on July 4, 2016. Sizemore ended his playing career following the 2016 season.
