Known for primarily throwing a sinking fastball, the right-hander stands 6' 6" (198 cm) tall, and weighs 250 lb (113 kg).

In 2007, his second season, the club promoted him from the Class A Lancaster JetHawks to the Double-A Portland Sea Dogs.

[9][10][11] Masterson converted to starting pitching in early 2007, after a stint as a relief pitcher for Short Season Lowell in 2006.

The next month, on May 20, he made his second appearance, pitching 6+1⁄3 innings, allowing three hits and one run with three walks and five strikeouts and picking up his first win in the Majors.

[14] After five starts with the major-league club, it was announced that he would stay in the majors through Daisuke Matsuzaka's return from the disabled list (DL) due to Bartolo Colón's back injury.

Masterson picked up the first postseason win of his career in Game 5 of the 2008 American League Championship Series (ALCS) against the Tampa Bay Rays, pitching a scoreless ninth inning in the Red Sox' 8–7 victory.

On July 31, 2009, Masterson was traded by Boston along with minor league prospects Nick Hagadone and Bryan Price to the Cleveland Indians in exchange for Victor Martinez.

Masterson enjoyed his first full season as a starter in 2010, but he once again failed to make an impact with the Indians and finished with a 6–13 record in 29 starts.

He pitched the first shutout of his professional career on June 9 of that season, a two-hit, 11–0 victory against Boston at Progressive Field, in which he struck out six and allowed two singles and two walks.

[20] Masterson finished the 2011 season with a 12–10 record, having career bests in ERA (3.21), innings pitched (216) and home runs allowed (11).

[21] Following the end of the season Masterson underwent surgery to repair a torn labrum in his non-throwing shoulder.

[25] He defeated Blue Jays' reigning NL Cy Young Award winner R. A. Dickey, acquired in the prior off-season from the New York Mets.

In his next start, his second win came against the reigning American League Cy Young winner, David Price of the Rays.

[29] On June 2, he completed an immaculate inning against the Red Sox, striking out Jonny Gomes, Grady Sizemore, and Stephen Drew in order on nine pitches.

[31][32] To honor their former teammate, all Indians players donned Masterson's high-sock style for the next game after his trade against the Mariners.

He won his Cardinals debut against the Milwaukee Brewers the next day, a 9–7 victory, in spite of allowing five runs, seven hits and three walks in six IP.

[34] A free agent after the 2014 season, Masterson agreed to a one-year deal with Boston worth $9.5 million on December 11.

His pitching arsenal included a fastball that reached 97 miles per hour (156 km/h), a sinker, a slider, and an occasional change-up.

Masterson and his wife Meryl founded the non-profit Fortress Foundation in 2013 with the help of business partner Matt Zappasodi and Cullinane Law.

[49] In 2013,[50] they worked with the Feed Their Future campaign with Mark Zimmerman from Moody Radio Cleveland and Bright Hope in Nairobi, Kenya.