He played in Major League Baseball for the Pittsburgh Pirates, Arizona Diamondbacks, Washington Nationals, Milwaukee Brewers, Chicago White Sox, St. Louis Cardinals, Minnesota Twins, Seattle Mariners, and Cincinnati Reds.

He posted a 15–6 record in 26 combined starts between Class-A Lynchburg and Double-A Altoona, and his 15 wins tied for third-most among all minor league pitchers.

Duke made his major league debut on July 2, 2005, against the Milwaukee Brewers, striking out nine and receiving a no-decision in the Pirates' 5–3 loss.

Duke's first full season with the Pirates in 2006 was as the new team ace, anchoring a very young rotation with Ian Snell.

Duke also threw 11 fewer pitches than his previous complete game effort, and recorded 14 ground-ball outs.

[5] Duke was named to the 2009 Major League Baseball All-Star Game, replacing the injured Matt Cain.

[5] On November 24, 2010, the Pittsburgh Pirates traded Duke to the Arizona Diamondbacks for a player to be named later, determined to be César Valdez.

[9] On May 28, 2011, Duke was activated off the disabled list and made his first start with the Arizona Diamondbacks, replacing Micah Owings in the rotation.

On July 15, Duke was relocated to the bullpen,[11] where he fared slightly better in a long-relief role, recording a 3.86 ERA in 25.2 innings, only striking out six while walking eight.

[14][15] On December 2, 2012, Duke re-signed with the Nationals on a one-year deal to serve as the team's long reliever.

Duke was signed as a free agent on January 15, 2014,[8] and invited to spring training by the Milwaukee Brewers for 2014 and made the roster as a left-handed relief specialist.

Duke finished the year strongly, recording a 2.45 ERA with 74 strikeouts against only 17 walks in 58.2 innings, appearing in 74 games and notching 12 holds.

[20] On July 21, 2016, the White Sox traded Duke to the St. Louis Cardinals for outfielder Charlie Tilson.

[21] On October 14, 2016, it was revealed that Duke underwent surgery to repair a forearm flexor muscle and UCL in his left arm, which was expected to sideline him for the entire 2017 season.

On July 30, 2018, Duke was traded to the Seattle Mariners for pitcher Chase De Jong and infielder Ryan Costello.