He played in Major League Baseball (MLB) for the New York Yankees, Minnesota Twins, and San Diego Padres during a career that spanned from 2007 through 2018.

Hughes began 2009 in the minors but later returned to the majors, eventually becoming a relief pitcher in June and pitching as a setup man for Mariano Rivera.

Upon returning to the Yankees' starting rotation in 2010, Hughes won 18 games and earned a berth on the American League All-Star team.

In 2013, Hughes had his worst season, posting a 4–14 win–loss record and a 5.19 earned run average; this performance led to his removal from the starting rotation.

[2] In his junior year (2003), he had a 12–0 record and posted an 0.78 earned run average (ERA) while striking out 85 batters in 72 innings.

[3] The Yankees were awarded this pick as compensation when free agent pitcher Andy Pettitte signed with the Houston Astros.

[4][5] In 2004, Hughes pitched five scoreless innings for the rookie Gulf Coast League Yankees, striking out eight hitters.

He was promoted to the Double-A Trenton Thunder of the Eastern League at the beginning of May after he had a 2–3 record and a 1.80 ERA with Tampa while striking out 30 batters in 30 innings.

[18] In his second major league start on May 1 against the Texas Rangers, he was maintaining a no-hitter through 6+1⁄3 innings before pulling his left hamstring while facing his future teammate Mark Teixeira.

[21] In his final start of the year, on September 27 against the Tampa Bay Devil Rays, he allowed one run in a season-high seven innings and earned the win in a 3–1 victory.

[24] He made his first postseason appearance in 2007 against the Cleveland Indians in the AL Division Series (ALDS), giving up one run in two innings in Game 1, a 12–3 loss.

[27] Prior to the 2008 season, it was reported by numerous news sources that the Yankees were thinking of including Hughes in a trade to the Minnesota Twins for Johan Santana.

[35] In his final start of the season, on September 24, he gave up two runs in eight innings and received a no-decision in a ten-inning, 6–2 victory over Toronto.

Hughes made his first start of the season on April 28 against the Detroit Tigers and pitched six scoreless innings, earning his first win since 2007 in an 11–0 victory.

[40] After he posted a 3–2 record and a 5.45 ERA in seven starts, Hughes was moved to the bullpen when Wang returned to the rotation in early June.

[41][42] Hughes pitched well, becoming the primary setup man to Mariano Rivera in July due to injuries to Brian Bruney and Dámaso Marte.

[51] Throughout the season, the Yankees occasionally had Hughes skip starts to limit his innings, in hopes that this would help him stay healthy.

[52] On April 21, Hughes carried a no-hitter into the eighth inning against the Athletics before allowing a leadoff single to Eric Chavez; he faced two more hitters prior to being relieved, having struck out 10 batters.

Hughes, after retiring the first batter he faced in the seventh inning, allowed a pair of singles to Scott Rolen and Matt Holliday before yielding to Matt Thornton; Rolen and Holliday scored the tying and go-ahead runs on Brian McCann's three-run double that proved decisive in the NL's 3–1 victory.

[59] Hughes had 18 wins (tied for fourth in the AL with Trevor Cahill and Justin Verlander behind Sabathia, who had 21, and Jon Lester and David Price, who both had 19), only 8 losses, and a 4.19 ERA while striking out 146 batters in 176+1⁄3 innings of work.

After opening the season 0–1 with a 13.94 ERA in three starts, Hughes was placed on the DL due to a dead arm syndrome.

On July 6, he made his first start in nearly 3 months, pitching five innings, allowing two earned runs, striking out and walking two batters, in a 5–3 loss to the Cleveland Indians.

[66] On August 2, in a rain-shortened game, Hughes threw his first career shutout as the Yankees defeated the White Sox 6–0 in six innings.

[47] On January 16, 2012, Hughes signed a one-year deal worth $3.25 million that included incentives, effectively avoiding arbitration.

In Game 3 of the ALCS against Detroit, Hughes allowed one run in three innings before exiting with back stiffness; he took the loss as the Yankees lost 2–1.

[86] His first win in a Twins uniform came in his fourth start, where he limited the Kansas City Royals to three earned runs over six innings in an 8-3 victory on April 20.

[91] Three starts later, he pitched his first complete game in over two years, throwing eight innings of two-run ball in a tough loss against the Red Sox in Boston.

[105] Upon his return from the disabled list, due to not being able to regain his complete stamina, Hughes agreed to head to the bullpen to build up strength.

[1] On May 27, 2018, the Twins traded Hughes, along with cash and the 74th pick in the 2018 MLB draft, to the San Diego Padres in exchange for minor-league catcher Janigson Villalobos.

[112]Hughes asserted that a hamstring injury he suffered in his rookie year permanently altered his pitching mechanics: "My stride, and things like that, have never quite been the same.