Sale, 30, entered Tuesday's game against the Indians with 1,995 strikeouts. He struck out the side in the first and reached the milestone in the third when he fanned rookie Oscar Mercado.
Sale finished with 12 strikeouts in 6⅔ innings, allowing five runs (three earned) on five hits and two walks. The Red Sox won 7-6 in 10 innings.
According to information provided by the Red Sox, Sale broke Hall of Famer Pedro Martinez's mark by getting to 2,000 strikeouts in 1,626 innings. Martinez did it in 1,711⅓ innings, Randy Johnson in 1,733⅓ and Max Scherzer in 1,784.
"It's cool. It's special," Sale said. "I'm not a guy who is really into his stats, but I respect it. I appreciate what it means. A lot of people put in a lot of hard work to help me get there."
Sale has struggled this season. He entered his 25th start at 6-11 with a 4.41 ERA. Still, he has the best strikeout-to-walk ratio (5.9 to 1) in the majors since 1920.
Sale is in his third season with Boston after spending seven with the Chicago White Sox. He opened 2019 with four straight losses and didn't get his first win until May 3.
The Associated Press contributed to this report.