McGehee was drafted by the Chicago Cubs in the tenth round of the 2003 Major League Baseball Draft out of Fresno State. McGehee was a September call-up for the Cubs in 2008, making his major league debut on September 2. He went 0 for 1 in his first game.

On March 31, 2009, it was announced that he would be a reserve infielder for the Brewers in 2009. When Ryan Braun got injured, third baseman Bill Hall played at Braun’s position in left field, while McGehee started at third base. When Rickie Weeks got injured, he made his first start at second base. With Bill Hall struggling at the plate, and Mat Gamel struggling on defense, he saw a lot of time at third base. He hit his first home run on June 14, 2009 off of Mark Buehrle of the Chicago White Sox; it was one of his two RBIs in the game. On June 29, 2009, he hit his first career grand slam off of New York Mets pitcher Brian Stokes, which came after he committed an error that led to two unearned runs. On July 4, McGehee had career highs of four hits and five RBIs against the Chicago Cubs. Although he came up short on the NL Rookie of the Year balloting for 2009, his solid season cemented him a starting job at third base for the Brewers in 2010.

In 2011, he batted .223 with 13 home runs, three of which came in the same game on August 3. All three were off of St. Louis Cardinals pitcher Edwin Jackson. He led all NL third basemen in errors, with 20.

On December 12, 2011, hours after the Brewers agreed to a contract with Aramis Ramírez, McGehee was traded to the Pittsburgh Pirates for José Veras.

On July 31, 2012, McGehee was traded to the New York Yankees for RHP Chad Qualls. The Yankees traded for 1B/3B McGehee after injuries to Alex Rodriguez and Mark Teixeira.

On August 28, 2012, McGehee was optioned to Class-A Charleston to make room on the 25-man roster for a recently acquired Steve Pearce. He was recalled when rosters expanded in September.

He signed a $1.5 million contract to play in Japan for the Tohoku Rakuten Golden Eagles on December 21, 2012. McGehee led the Golden Eagles to their 1st Japan Series title. Also leading the way were Japan Series MVP Manabu Mima, current Yankees star Masahiro Tanaka, and fellow former MLB outfielder Andruw Jones. In 144 games, mostly at third base, McGehee hit .292 with 28 HR and 93 RBI.

McGehee’s period in Japan paid off, and on December 18, 2013, McGehee signed a one-year, $1.1 million deal with the Miami Marlins to start at third base. McGehee hit his first Marlins home run on May 10, despite hitting .309 with 23 RBI in 36 games before. It was in Miami that Casey earned his nickname “Hits McGehee.” In 159 games of 2014, McGehee grounded into an MLB-leading 31 double plays while batting .289 with 4 home runs and 76 RBI, winning the Major League Baseball Comeback Player of the Year Award for the National League.

On December 19, 2014, McGehee was traded to the San Francisco Giants in exchange for minor league pitchers Kendry Flores and Luis Castillo. He began the 2015 season as the Giants starting third baseman but struggled and was designated for assignment on May 24. On May 26, McGehee accepted an assignment to the Giants AAA team, the Sacramento River Cats, but was recalled by the Giants on June 5 after batting .357 (15-for-42) with two homers and three doubles. After appearing in a total of 49 games for the Giants and batting .213 he was designated for assignment again on June 30.

On July 10, 2015, the Miami Marlins signed McGehee to a one-year contract.

On February 23, 2016, the Detroit Tigers signed McGehee to a minor league contract. On March 28, 2016, McGehee was released by the Tigers. On March 30, the Tigers re-signed McGehee to a minor league contract. On June 18, 2016, the Tigers purchased McGehee’s contract from the Toledo Mud Hens. In early August 2016, McGehee was called up to the major leagues by the Tigers following an injury to Nick Castellanos.

On December 3, 2016, McGehee signed a one-year contract with the Yomiuri Giants that includes a club option for the 2018 season.