Lowe was part of perhaps the most lopsided trade in team history that favored the Red Sox, coming to Boston with catcher Jason Varitek in exchange for Heathcliff Slocumb at the trade deadline in 1997. Primarily used as a relief pitcher early in his Red Sox career, he succeeded Tom Gordon as the team closer after the latter was placed on the disabled list in June 1999. From there, he recorded 15 saves that season, then recorded another 42 saves in 2000 to earn the honor of closing for the American League All-Star squad that summer. Although Lowe saved another 24 games the following season, he proved less effective, blowing six saves; with that, the Red Sox made the decision to move him to the starting rotation, which proved to be the right choice.
In 2002, Lowe won 21 wins in 32 starts and was chosen as the starter for that season’s AL All-Star team, becoming the first player to start an All-Star game after appearing as the closer in a previous Mid-Summer Classic. He also finished third in the vote for the Cy Young Award behind Barry Zito of the Oakland Athletics and teammate Pedro Martinez. The highlight of his season for Lowe, however, was a no-hitter thrown on 27 April against the Tampa Bay Devil Rays in a 10-0 win, the most lopsided no-hitter in major league history, in which he allowed just one batter to reach base. With that, he became the third player in major league history to have both a 40-save season and a no-hitter on his resume as well as the first to record a no-hitter following a 40-save season. He also became only the third player to have both a 20-win season and a 40-save season and the only one to first record the 40 saves.
While Lowe won 31 games over his last two seasons with the Red Sox in 2003 and 2004, his ERA ballooned as control issues began to plague him. However, he is well remembered for his post-season efforts in both seasons. In the deciding fifth game of the 2003 Division Series versus the Athletics, Lowe came in to relieve closer Scott Williamson and recorded the last three outs of the game, ending it with a strikeout of Terrence Long to send Boston to the Championship Series. The following year, he earned the win in all three of the deciding series games, capped with seven innings of shutout baseball in Game Four of the World Series versus the Cardinals for the team’s first world championship in 86 years.