Hughes was drafted by the Pittsburgh Pirates in the fourth round of the 2006 Major League Baseball draft out of Long Beach State University. He started his pro career as a starting pitcher in 2006 with the Williamsport Crosscutters and the Hickory Crawdads. He spent the 2007 season with Hickory, where he was 8-9 with a 4.64 ERA, and led the league with 27 wild pitches in 145.1 innings. He spent the 2008 season with the Lynchburg Hillcats and the Altoona Curve. He led the league in wild pitches. In 2009, Hughes pitched for the Gulf Coast League Pirates and Altoona, and was a combined 1-6 with three saves and an ERA of 3.61. In 2010, Hughes pitched for Altoona, and was Pitcher of the Week in the Eastern League on May 17. For the season he was 12-8, and his 12 wins tied for the second-most in the league, were the third-most in a season in club history, and tied for first among all Pittsburgh minor leaguers. He also led the league in wild pitches, with 15 in 150.2 innings. Hughes started the 2011 season in the Altoona rotation, but was promoted and moved to the bullpen with the Triple-A Indianapolis Indians. Between the two teams in 2011, he was 6-5 with a 3.28 ERA in 48 games covering 104.1 innings. When Hughes was promoted to the majors in September 2011, he became the 41st major leaguer in Long Beach State history. He appeared in 12 games, going 0–1 with a 4.09 ERA. On April 25, 2012, Hughes was recalled from Triple-A Indianapolis. A day later he was optioned back but recalled again on May 1. On August 12, Hughes was optioned back to Indianapolis to make room for Juan Cruz coming off the Disabled list. He was recalled again on August 14. Hughes finished the season with 66 appearances, going 2–2 with two saves and a 2.85 ERA. He led all NL rookie relief pitchers in ERA, and was second in games and innings pitched. The 2013 season was a setback for Hughes, as he battled injuries and inconsistency throughout the year, resulting in a 2–3 record in 29 appearances and a 4.78 ERA. As a result, he also spent time in AAA, pitching in 18 games, with a record of 1-0 with two saves and an ERA of 0.43 in 21 innings. In 2014 Hughes played in 63 games and posted a 7–5 record, with a career-low 1.96 ERA. In 64 1/3 innings, he allowed 51 hits and had a 1.09 WHIP. The 2015 season was another successful one for Hughes, as he put together a 3–1 record in a career-high 76 games, with a 2.28 ERA and a 1.33 WHIP. In 2016, he was 1-1 with one save and had an ERA of 3.03 in 67 games for the Pirates. In innings, he struck out 34. Hughes was released on March 29, 2017.
Milwaukee Brewers
Hughes signed a one-year contract with the Milwaukee Brewers on April 2, 2017. In his season in Milwaukee, he posted an ERA of 3.02 in 67 games. He was 5-3 with one save in innings.
Cincinnati Reds
On December 26, 2017, Hughes signed a two-year contract with the Cincinnati Reds, with a $3 million club option for 2020. In his first season in Cincinnati, in 2018 Hughes posted a career-low 1.94 ERA and 1.017 WHIP in 72 appearances covering 78.2 innings. He finished 4–3 with 7 saves. In the seven seasons from 2012–18, his 2.66 ERA ranked fourth-best among all major league relief pitchers who made at least 440 appearances, Kenley Jansen, and Tony Watson ), and among all relievers he ranked tied for second with 65 GIDPs induced, tied with Jim Johnson ), and 10th with a ground ball rate of 62.0%. In the first part of 2019, before he was put on waivers, Hughes was 3-4 with one save and a 4.10 ERA in 47 appearances covering 48.1 innings.
Philadelphia Phillies
On August 15, 2019, Hughes was claimed off waivers by the Philadelphia Phillies. On August 17 Hughes made his debut against the San Diego Padres. In 2019 for the Phillies, he was 2-1 with a 3.91 ERA, as in 25 relief appearances he pitched 23.0 innings. As of 2019 he had the best range factor/9 innings pitched of all active pitchers, at 2.69.
Houston Astros
On February 17, 2020, the Astros signed Hughes to a minor league contract. He was released on March 19.
New York Mets
On June 30, 2020, Hughes signed with the New York Mets.
Personal life
Hughes is married to Kelly Hughes. They married in 2011. The couple have a son, William, who was born in 2016. Hughes is a Christian.
