While attending Florida International University on an athletic scholarship Lowell was drafted by the New York Yankees in the 1995 amateur draft. Lowell graduated in 1997 and made his professional debut in the 1998 season. He was traded to the Marlins on February 1, 1999. While waiting for spring training, he had testicular cancer and surgery was performed on February 21. He returned to the lineup on May 29, and finished his rookie season with a .253 BA, 12 home runs and 47 runs batted in.

Lowell was on pace to have a great season in 2003, but a groin injury prevented him from playing in 32 games, and he ended with 32 homers and 105 RBI. In 2004 he hit a career high .293 with 27 home runs and 85 RBI. Despite a disappointing 2005 season in which he hit .236 with only 8 homers and a .298 on-base percentage, Lowell earned his first Gold Glove Award. Although the Red Sox took on Lowell and his contract only because the Marlins would not trade Beckett without relieving themselves of Lowell's salary, Lowell has fared bettered than expected as a member of the 2006 Red Sox, leading the league in doubles and providing solid defense.

Lowell is also known as a practitioner of the hidden ball trick, and, as of 2005, had recorded Major League Baseball's two most recent successful outs with the maneuver, on Arizona's Luis Terrero in 2005 and Montreal's Brian Schneider in 2004.

In an eight-year career, Lowell is a .272 hitter with 143 home runs and 578 RBI in 989 games. He wears number 25 for the Red Sox.

Mike Lowell was one of the Puerto Rican players to agree to play for Puerto Rico in the 2006 MLB World Baseball Classic, joining catchers Ivan Rodriguez and Sandy Alomar, Jr., 1st baseman Carlos Delgado, 2nd baseman Jose Vidro, outfielders Bernie Williams, Carlos Beltran and Jose Cruz, Jr. and Pitchers Javier Vazquez, Joel Pineiro, J.C. Romero and Kiko Calero amongst others representing the island in a team managed by Saint Louis Cardinals third base coach Jose Oquendo.

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