He has previously played in Major League Baseball (MLB) for the Boston Red Sox, Miami Marlins, and Washington Nationals.

Barnes spent most of the 2014 season with Triple-A Pawtucket, where he appeared in 23 games (22 starts) compiling an 8–9 record with a 3.95 ERA and 103 strikeouts in 127+2⁄3 innings pitched.

[15] He made his MLB debut the next day, pitching three scoreless innings of relief in a 4–1 Boston loss to the Baltimore Orioles.

[16] He finished the rest of the season with Boston, making a total of five MLB appearances (all in relief) while giving up four runs in nine innings pitched (4.00 ERA).

[18] During the 2016 ALDS, Barnes made his postseason debut, pitching 1+2⁄3 innings in Game 2 against the Cleveland Indians; he gave up three hits and one unearned run.

[20] The next day, Barnes received a four-game suspension for "intentionally throwing a pitch in the area of the head of Manny Machado.

"[21][22] For the 2017 season, Barnes made 70 relief appearances with Boston, compiling a 7–3 record, plus one save, with a 3.88 ERA and 83 strikeouts in 69+2⁄3 innings pitched.

[17] In the postseason, he made 10 appearances while allowing one earned run in 8+2⁄3 innings as the Red Sox went on to win the World Series over the Los Angeles Dodgers.

Overall with the 2020 Red Sox, Barnes appeared in 24 games, all in relief, compiling a 1–3 record with 9 saves, 4.70 ERA, and 31 strikeouts in 23 innings pitched.

[17] In early December 2020, Barnes and the Red Sox reached a one-year deal for the 2021 season, worth a reported $4.5 million.

[29] On July 11, the Red Sox reached an agreement with Barnes on a two-year contract extension, including a team option for the 2024 season.

[35] It was later revealed that Barnes had cut off the tip of the thumb on his left (non-throwing) hand with a knife while cooking, which contributed to his late season struggles.

On July 14, it was announced that Barnes would undergo femoral acetabular impingement surgery on his left hip, and likely miss the remainder of the season.

[45] He cleared waivers and was sent outright to the Triple–A Rochester Red Wings on May 9;[46] however, he subsequently rejected the assignment and elected free agency on May 10.

[45][47] Barnes began holding an annual baseball clinic at the Newtown, Connecticut, Youth Academy for elementary school students in December 2013.