He was traded to the Boston Red Sox prior to the 2017 season and was a key member of their pitching rotation that helped the team win the 2018 World Series.

After reaching 300 strikeouts in a single season for the first time in 2017, he was selected as the AL Sporting News Starting Pitcher of the Year.

In 2008, he was an All-Star for the La Crosse Loggers of the Northwoods League, and it was during his time in Wisconsin that coaches suggested he adopt his now distinctive low three-quarter arm angle.

[16] Sale pitched in four games with a 2.25 ERA in four innings, while giving up three hits and one earned run while walking two and striking out four during his tenure with the Dash.

[25] On March 7, 2013, Sale and the White Sox agreed on a five-year, $32 million contract with two option years depending on the team.

[33] During a game against the Angels on June 7, 2014, Sale had a 5–0 lead but surrendered 5 runs all in the 7th inning that featured a grand slam by Mike Trout.

[36] During a game against the Kansas City Royals on April 23, 2015, Sale was warned by home plate umpire Sam Holbrook after hitting Mike Moustakas with a pitch.

On June 30 against the St. Louis Cardinals, Sale struck out 12 batters to tie a major league record with his eighth consecutive start of 10 or more strikeouts.

Kansas City Royals manager Ned Yost named him the starter for the 2016 Major League Baseball All-Star Game.

Sale was not pleased about the idea, as he felt the pullover jerseys were too baggy and interfered with his pitching mechanics, and this prompted him to use scissors to tear up the throwback uniforms that had been laid out in the clubhouse while the rest of the team was on the field for practice.

[45] With the 2017 Red Sox, Sale began the season by striking out 10 or more batters in eight consecutive starts, tying the major league record he already shared with Pedro Martínez.

In the first postseason appearance of his MLB career, Sale was the starting pitcher in Game 1 of the Division Series against the Houston Astros.

[53] Sale then pitched in relief in Game 4, allowing four hits and two runs in 4+2⁄3 innings and again taking the loss, as the Astros eliminated the Red Sox with a 5–4 win.

However, the Rays scored six runs in the eighth inning off of Boston's bullpen, defeating the Red Sox, 6–4, and leaving Sale with a no decision.

[59] On July 31, Sale was placed on the disabled list due to left shoulder inflammation;[60] at that point in the season, he had an 11–4 record with 2.04 ERA in 22 starts.

[64] Sale made two appearances, including one start, in the American League Division Series, allowing two earned runs in 6+1⁄3 innings.

During Game 4, with the Red Sox trailing by four runs, Sale gained notoriety for shouting at his teammates in the dugout, imploring them to generate more offense (the team had only one hit through the first six innings).

[65] In Game 5, Sale became a World Series champion for the first time, closing out the final inning, including a series-ending strikeout of Manny Machado.

"[69] On May 8, Sale threw an immaculate inning for the first time in his career, striking out three straight Orioles batters on a total of nine pitches.

[77][78][79] After meeting with James Andrews on August 19, it was determined that Sale did not need surgery; however, the inflammation in his elbow was expected to end his season.

[82] On February 27, 2020, Red Sox manager Ron Roenicke announced that Sale would not be ready for Opening Day due to his progress in spring training being hampered by pneumonia.

", columnist Tyler Kepner discussed the Tommy John surgery of both Sale and Noah Syndergaard in a time when the coronavirus pandemic had led federal, state, and local authorities to restrict medical procedures to essential services only.

[103] In the postseason, Sale made three starts, taking one loss and allowing 10 runs (eight earned) in nine innings as the Red Sox advanced to the American League Championship Series.

[103] In February, Sale sustained a right rib stress fracture while throwing batting practice at Florida Gulf Coast University.

[105] On July 1, Sale pitched for the Portland Sea Dogs in a rehabilitation assignment, allowing one run on four hits in four innings while striking out seven batters.

[106] During a rehab start in Triple-A on July 7, a video captured Sale destroying items in the dugout tunnel after he issued five walks and allowed one run in 3+2⁄3 innings.

[112] Chief Baseball Officer Chaim Bloom commented that the Red Sox needed to find whoever had a "Chris Sale voodoo doll", referring to his list of injuries since the 2019 season.

On June 1, he was removed from a game against the Cincinnati Reds after experiencing shoulder discomfort;[114][115] he was placed on the injured list the next day.

[122][123] Sale was selected to the 2024 Major League Baseball All-Star Game roster as a reserve, alongside teammates Marcell Ozuna and Reynaldo López.

[124][125] On August 13, against the San Francisco Giants, Sale recorded his eleventh game with no earned runs, 3 or fewer hits allowed, and 12+ strikeouts, tying Sandy Koufax for third-most all-time, behind Nolan Ryan (23) and Randy Johnson (13).