In a June 8 win over the Houston Astros, Sale struck out 14 batters. On June 19, Sale had his 5th consecutive game with 12 or more strikeouts, tying a major league record. Also, on June 19, Sale had his 6th consecutive game with 10 or more strikeouts. 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. He shared the record with Pedro Martínez, who accomplished the feat while pitching for the Boston Red Sox in 1999.

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. He allowed nine hits and seven runs in five innings, taking the loss. Sale then pitched in relief in Game 4, allowing four hits and two runs in 4 ⁄3 innings and again taking the loss, as the Astros eliminated the Red Sox with a 5–4 win. Sale had a postseason ERA of 8.38 while striking out 12 and walking one in 9 ⁄3 innings pitched. Despite being the favorite to win the AL Cy Young award throughout the entire regular season, Sale finished second in the voting behind Corey Kluber, who won the award for a second time. Despite pitching more innings and recording more strikeouts than anyone else in baseball that season, Sale’s subpar finish to the season after a blistering start (13–4 with a 2.37 ERA and 211 strikeouts in 148 ⁄3 innings (21 starts) before August 1, but 4–4 with a 4.09 ERA in 66 innings (11 starts) and 13 home runs allowed after August 1) combined with Kluber’s masterful run after an abysmal start to the season followed by a month-long stint on the DL (3-2 with a 5.06 ERA in 37 ⁄3 innings (six starts) before May 2, but 15–2 with 224 strikeouts, a 1.62 ERA in 166 ⁄3 innings (23 starts), 4 complete games and a 9.74 K/BB ratio after June 1) cost Sale his best chance yet at winning the Cy Young. He did, however, finish 9th in the AL MVP voting, becoming the first Red Sox pitcher to finish that high since Pedro Martínez finished fifth in 2000.

Like many top college players, Sale spent the NCAA offseason pitching in wooden bat summer leagues. 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. In the summer of 2009, Sale pitched for the Yarmouth-Dennis Red Sox of the Cape Cod Baseball League. He had a record of 4–2 and an earned run average of 1.47 with Yarmouth-Dennis, with 57 strikeouts as well. Sale was named the MVP of the East Division squad in the Cape Cod All-Star Game, and received the league’s Outstanding Pitcher award.

Sale was drafted by the White Sox with the 13th overall selection in the first round of the 2010 MLB Draft. Once Sale signed with the White Sox in 2010, he was assigned to the White Sox’ Class A affiliate Winston-Salem Dash. Sale pitched in four games for the Dash with a 2.25 ERA in four innings. Sale gave up three hits and one earned run while walking two and striking out four during his tenure with the Dash. Sale was then promoted to the White Sox’ triple-A affiliate Charlotte Knights. While there, Sale pitched in seven games for the Knights with a 2.84 ERA in 6 1/3 innings. Sale gave up three hits and two earned runs while walking four and striking out 15 while with the Knights.

Sale was called up to the majors for the first time on August 4, 2010, and made his MLB debut August 6, against the Baltimore Orioles in the eighth inning. He was the first 2010 draft pick to be promoted to the majors and got his first major league save on September 1, 2010, against the Cleveland Indians. In 21 appearances in his rookie year, Sale went 2–1 with a 1.93 ERA, 32 strikeouts, and 4 saves.

During 2011, Sale made 58 appearances out of the bullpen with a 2–2 record, a 2.79 ERA, 8 saves, and 79 strikeouts.

During the 2012 season, Sale compiled a 17–8 record, a 3.05 ERA, and 192 strikeouts in 192 innings pitched. He ended up finishing sixth in voting for the AL Cy Young Award.

Sale throws with a “funky” sidearm throwing motion. He is nicknamed “The Condor” because his unorthodox delivery makes him resemble a California condor. His moniker was first coined on SB Nation’s South Side Sox site on April 17, 2012.

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.

On May 12, 2013, Sale threw a one-hit shutout during a 3–0 Sox victory over the Los Angeles Angels of Anaheim. Sale took a perfect game into the seventh inning. With one out in the top of the seventh inning, Mike Trout singled up the middle for the only hit of the game. Sale finished the game with 7 strikeouts and no walks, allowing Trout as the only base runner. Sale began the 2013 season with a 6–8 record and a 2.85 ERA. He was named an All-Star for the 2nd season in a row. Sale came on to pitch for the 2nd and 3rd innings, allowing no hits, no runs, no walks and striking out two NL hitters. He was named the winning pitcher for the American League, which won the game 3–0.

On April 21, Sale was placed on the 15-day disabled list after sustaining a flexor strain in his left (pitching) elbow. During his first start off the disabled list against the New York Yankees on May 22, 2014, Sale retired the first 17 batters in a row before allowing a single by Zoilo Almonte. He struck out 10 in 6 innings pitched as the White Sox won the game 3–2. 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. Sale continued his dominance on the mound, winning eight of his first nine decisions and carrying an 8–1 record and 2.08 ERA into the All-Star break.

Sale started the 2015 year on the disabled list due to a foot injury. He returned on April 12, pitching 6 innings with 8 strikeouts in a 6–2 victory over the Minnesota Twins. 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. Later on, Sale was involved in a bench-clearing brawl after his teammate Adam Eaton grounded out to Yordano Ventura. Sale was one of five players to be ejected for his role in the brawl as the White Sox lost to the Royals 2–3 in 13 innings. On April 25, Sale was suspended for 5 games.

On July 23, prior to a game against the Detroit Tigers, the White Sox were set to wear throwback uniforms based on the design implemented by Bill Veeck during his second ownership of the White Sox. 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. Shortly after, the White Sox sent Sale home and scratched him from his start that day, and the White Sox took the field in their 1982-86 throwbacks instead. The next day, on July 24, the White Sox suspended Sale for five days. Sale made 32 starts in 2016, finishing with a 17–10 record, a 3.34 ERA, and 233 strikeouts, in 226.2 innings pitched. He also pitched 6 complete games and hit 17 batsmen with pitches, in which both categories led the MLB.

On December 6, 2016, the White Sox traded Sale to the Boston Red Sox for Yoan Moncada, Michael Kopech, Luis Alexander Basabe, and Victor Diaz. Upon joining Boston, Sale switched his uniform number from 49 to 41 out of respect for Tim Wakefield.

Notes: Through 2016 season. Per Baseball-Reference.com.

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. After going 11–4 with a 2.75 ERA and an MLB leading 178 strikeouts in the first half of 2017, Sale was named the American League’s starting pitcher at the All-Star Game for the second consecutive season, the first pitcher to do so since Randy Johnson started for the National League in 2000 and 2001 and the first for the AL since Dave Stieb in 1983–84. Sale pitched two scoreless innings in the game, striking out two batters. In his second start after the All-Star break, Sale joined Johnson, Martínez and Nolan Ryan as the only four pitchers to have struck out 200 batters in their first 20 starts of a season. Pitching against the Toronto Blue Jays on August 29, Sale recorded his 1,500th career strikeout, becoming the fastest to do so in terms of innings pitched. At that point, he had reached 1,290 innings, surpassing Kerry Wood, who had done so in 1,303 innings. Sale reached 300 strikeouts for the season when he struck out 13 batters on September 20. It was the first 300 strikeout season since Clayton Kershaw in 2015, and the first in the American League since Martínez in 1999.

On March 23, 2019, Sale signed a five-year, $145 million extension with the Red Sox. Sale earned $15 million in 2019 via a club option in his prior contract, with the extension covering 2020 through 2024 plus a vesting option for 2025. Manager Alex Cora named Sale as Boston’s starting pitcher for 2019 Opening Day. Sale started the season 0–4 with an 8.50 ERA, a performance he called “flat-out embarrassing.” 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. On May 14 against Colorado, Sale struck out 17 batters, a new career-high; he left after seven innings and received a no decision as Boston lost in extra innings. He pitched his second immaculate inning on June 5, in a complete game shutout against Kansas City, striking out 12. On August 13, Sale recorded the 2,000th strikeout of his major league career; he reached that mark in 1,626 innings pitched, the fewest innings needed to accomplish the feat in MLB history. On August 17, Sale was placed on the 10-day injured list due to left elbow inflammation, retroactive to August 14. After meeting with Dr. 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. On September 1, the Red Sox moved him to the 60-day injured list. For the 2019 season, Sale had a 6–11 record with 4.40 ERA and 218 strikeouts in 147 ⁄3 innings. He had 14 games with 10 + strikeouts including a period from April 21 to June 26, when he had 10 + strikeouts in 10 out of 13 starts

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. Two weeks later, the season was delayed due to coronavirus pandemic concerns. On March 19, the team announced that Sale would undergo Tommy John surgery, thereby ending his 2020 season. On March 30, the Red Sox announced that Sale successfully underwent the surgery, which was performed in Los Angeles. On June 28, days before the restart of preseason training, the team placed Sale on the 45-day injured list (reduced from 60-day for 2020).