He began 2002 with the Tucson Sidewinders of the Class AAA Pacific Coast League (PCL) and was 4–1 with a 2.72 ERA when, on May 17, he had Tommy John surgery and missed the rest of the season.

[6] He made his MLB debut with the Diamondbacks on May 4, 2003, against the Atlanta Braves, picking up the loss in a two-inning appearance in extra innings.

He made his first start on May 17 against the Pittsburgh Pirates, but only lasted 4 and 2⁄3 innings while allowing seven earned runs to take the loss.

He returned to the minors after the appearance, where he made 23 starts for Tucson, with a 9–5 record and 3.34 ERA, earning him PCL All-Star honors.

[7] On December 1, 2003, Capuano was traded to the Milwaukee Brewers (along with Craig Counsell, Lyle Overbay, Junior Spivey, Jorge de la Rosa and Chad Moeller) for Shane Nance, Richie Sexson and minor leaguer Noochie Varner.

In 2006, Capuano continued his excellent pitching by taking over as the team's new ace with Ben Sheets injured and was named to the 2006 Major League Baseball All-Star Game as a replacement for Tom Glavine.

[10] The Brewers non-tendered Capuano following the 2008 season, making him a free agent but re-signed him to a minor league deal shortly after.

[17] Capuano started the Brewers' June 3, 2010, game against the Florida Marlins in Miami, giving up three runs on seven hits in 32⁄3 innings while striking out four and walking one.

He got the start on April 16 due to an injury to Zack Greinke but suffered a strained left calf and only lasted three innings.

[31] He pitched for the Tulsa Drillers of the Texas League and the Colorado Springs Sky Sox of the PCL, making a total of four starts between the two teams.

[34] Wearing a Yankee uniform, he started two games for the MLB All Stars, allowing just one earned run on five hits and striking out seven batters.

[39] The Yankees then recalled him again on August 18 to take the place of Bryan Mitchell, who had been injured by a line drive during a spot start the previous evening.

[46] Capuano was generally more of a finesse pitcher who relied on his deceptive delivery, accuracy and ability to change speeds.

He threw his fastball in the upper 80s on average, and would sometimes reach the low 90s as well, especially early in games or later in his career during relief appearances.

His father, Frank Capuano, was also a standout athlete who played as a shortstop and centerfielder for American International College in Springfield, Massachusetts.

While a member of the Milwaukee Brewers, Capuano, along with teammates J. J. Hardy, Bill Hall, and Jeff Suppan, appeared in an episode of The Young and the Restless on June 20, 2007.

While at MIT, he became a strategy and development advisor for Proteus Motion, Inc., focusing initially on its flagship fitness and training technology platform.

[49][50] Chris was appointed director of operations with the Major League Baseball Players Association (MLBPA) on July 5, 2019.