He played in Major League Baseball (MLB) for the Philadelphia Phillies, Kansas City Royals, Oakland Athletics, Washington Nationals, and Los Angeles Dodgers.

[6] In Game 6 of the 2010 National League Championship Series, Madson was the losing pitcher when he gave up a solo home run to Juan Uribe in the eighth inning of a 3–2 loss to the San Francisco Giants.

as of August 21, 2011[update], Madson converted 23 saves in 25 opportunities and retained the closer role even after Lidge returned from the DL in July.

[9] Before the end of spring training, Madson had a torn ligament in his right elbow, requiring Tommy John surgery, and missed the entire 2012 season.

[20] Madson was the last player added to the Royals' 25-man roster, beating out Brian Flynn for the final bullpen position in a decision that manager Ned Yost called "the hardest ...

[21] He made his first major league appearance in over three years on April 6, 2015, pitching a scoreless ninth inning in the Royals' 10-1 Opening Day defeat of the Chicago White Sox.

[23] With Wade Davis and Greg Holland unavailable, Madson earned the first save of this new stage of his career on August 9, holding the White Sox scoreless in the ninth inning for a 5-4 victory.

[24] By the end of the month, Madson began to experience fatigue and "dead arm", and he was put on rest in order to be ready for a postseason push.

On July 16, 2017, Madson was traded to the Washington Nationals, along with Sean Doolittle, for Blake Treinen, Sheldon Neuse, and Jesus Luzardo.

On August 31, 2018, Madson was traded to the Los Angeles Dodgers in exchange for minor league pitcher Andrew Istler.

[30][31] Since his Tommy John surgery, at the suggestion of his Anaheim Angels teammates, Madson has trained with EVO Ultrafit in Phoenix, Arizona, and carries around a POV Sport, an electrical modality, with him at all times during the season.