He played in Major League Baseball (MLB) for the Los Angeles Dodgers, Chicago Cubs, and Atlanta Braves.

In addition to his hitting prowess, DeWitt was an effective pitcher, winning a Missouri high school record 27 consecutive games and losing only 1.

During spring training in 2008, injuries to Nomar Garciaparra, Andy LaRoche, and Tony Abreu, the team's top three projected third basemen, led to DeWitt getting a chance to play with the big league club.

He became the Dodgers opening day starting third baseman and in his first at bat he singled off San Francisco Giants pitcher Barry Zito and went 5 for 9 with 3 walks in the 3-game series.

[2] Immediately following the team's acquisition of third basemen Casey Blake from the Cleveland Indians,[3] DeWitt was optioned to the Las Vegas 51s, Dodgers' AAA minor league team, on July 26, 2008 and began to learn the second base position to better increase the clubs' depth at the position.

This move proved wise as Jeff Kent became sidelined late in the season and DeWitt was recalled to Los Angeles to start at second base prior to the September 1st expansion of the rosters.

On July 31, 2010, DeWitt was traded along with minor league pitchers Brett Wallach and Kyle Smit to the Chicago Cubs for Ted Lilly and Ryan Theriot.

He displayed typically low strikeout and walk rates, at 12.8% and 4.9% respectively, while also receiving 17 starts in the outfield, playing there for the first time in his career.

[10] In December 2012, DeWitt signed a minor league contract with the Atlanta Braves and was a non-roster invitee to spring training in 2013.

April 2008 was declared "Blake DeWitt Month" in his hometown of Sikeston, Missouri by Mayor Mike Marshall.