Derek Lowe was drafted by the Seattle Mariners in the 1991 MLB Draft and they immediately assigned him to their rookie league team, where he had a 2.41 ERA. He spent the next several years working his way through several minor league teams and made his major league debut in 1997, working in relief against the Toronto Blue Jays in April.

Seattle had a lineup that included Ken Griffey Jr, Edgar Martinez, and Randy Johnson in their prime and a young A-Rod. But they had a weak bullpen and a terrible closer. They therefore packaged Lowe and catcher Jason Varitek into a deal with the Red Sox for Heathcliff Slocumb.

Lowe had pitched in only 12 games with a 6.96 ERA, and Varitek had never played in the majors. Meanwhile, Slocumb was a widely respected closer. In retrospect, it was one of the most one-sided trades in baseball history.

Derek came into his own in 1999 after being transferred into the closer's role, finishing the season with a 2.63 ERA. He had his best season as a closer in 2000 when he led the American League with 42 saves and recorded a 2.56 ERA.

Despite recording 24 saves early in the 2001 season, Lowe lost the closer's job soon after the trading deadline when the Red Sox acquired Ugueth Urbina. He was left in limbo, and asked manager Joe Kerrigan to return him to the starting rotation.

As a starter in 2002, Derek posted a 21–8 record, a 2.58 ERA, and finished third in "Cy Young Award" voting behind Barry Zito and teammate Pedro Martínez. He also no-hit the Tampa Bay Devil Rays at Fenway Park on April 27th, becoming the first pitcher to do so at Fenway Park since Dave Morehead in 1965.

In 2004, he would finish 14–12 with a 5.42 ERA, spending part of the season demoted to the Red Sox bullpen. During the postseason he would rebound with a 3–0 record and 1.86 ERA. He was the winner in the final game of ALDS against the Anaheim Angels, ALCS against the New York Yankees, and World Series against the St. Louis Cardinals.

In January 2005, Lowe finalized a $36 million, four-year contract with the Los Angeles Dodgers. Despite his signing with a new team, Lowe wore a Red Sox uniform, with his career-long number of 32, during the Red Sox World Series ring ceremony after already making a start for the Dodgers.

Lowe has advocated for various causes to fight cancer. Himself a survivor of squamous cell carcinoma, Lowe has worked with the Melanoma Foundation of New England, the National Council on Skin Cancer Prevention, and The Prostate Cancer Foundation.