He played in Major League Baseball (MLB) for the Boston Red Sox, Oakland Athletics, Chicago Cubs, Washington Nationals, and St. Louis Cardinals.

Less than two years after being diagnosed with lymphoma, Lester started and won the final game of the 2007 World Series for the Red Sox and, in May 2008, pitched a no-hitter against the Kansas City Royals.

Lester started the opening game of a playoff series 12 times, which was a record for the most in baseball history until Justin Verlander passed him in 2023.

[4] Lester quickly moved through the Red Sox organization, posting an 11–7 win–loss record, a league-leading 2.61 earned run average (ERA) and a league-best 163 strikeouts for the Portland Sea Dogs of the Class AA Eastern League in 2005.

The Texas Rangers had demanded Lester be part of the proposed but ultimately rejected deal before the 2004 season for Alex Rodriguez.

[5] With a rash of injuries and general ineffectiveness of several Red Sox starters, the team recalled Lester on June 10 to make his major league debut against the Texas Rangers.

On August 31, it was reported that Lester had been diagnosed with enlarged lymph nodes and was being tested for a variety of ailments, including forms of cancer.

[6] A few days later, doctors at Massachusetts General Hospital confirmed that Lester had a treatable form of anaplastic large cell lymphoma.

[11] On September 26 against the Oakland Athletics at Fenway Park, Lester gave up what would turn out to be the final career home run by Hall of Fame catcher Mike Piazza.

In the 2007 World Series against the Colorado Rockies, Lester won the series-clinching Game 4 for the Red Sox, pitching 5⅔ shutout innings, giving up three hits and three walks while collecting three strikeouts.

[12] To honor Lester's comeback from lymphoma, the Boston Baseball Writers' Association of America voted him the 2007 Tony Conigliaro Award.

Lester threw 130 pitches in the game, allowing only two walks and striking out nine batters, and was charged with a throwing error on a pickoff attempt in the second inning.

Lester was also a key figure in the Red Sox' victory over the Angels in the American League Divisional Series, pitching 14 innings without allowing an earned run.

[18] Lester also received the 2008 Hutch Award, given to the Major League player who "best exemplifies the fighting spirit and competitive desire" of Hutchinson.

Lester struggled along with the rest of the team, losing his last three decisions, including giving up eight runs in a start against the New York Yankees.

In the end of the 2011 season, Lester, Josh Beckett, and John Lackey were at the center of a controversy about players drinking alcohol during games.

[27] On October 3, 2013, Lester was named as the starting pitcher for Game 1 of the 2013 ALDS against the Tampa Bay Rays in Boston's first return to the postseason since 2009.

[35] On July 31, 2014, Lester and Jonny Gomes were traded to the Oakland Athletics for Yoenis Céspedes and a competitive round 2015 draft pick.

The move reunited Lester with former teammates Jed Lowrie, Coco Crisp, Brandon Moss and Josh Reddick.

Lester, however, received a no decision, as the bullpen blew the lead, and the Royals made a dramatic comeback to win the game in 12 innings.

[43] On May 27, 2015, matchup with the Washington Nationals, Lester hit a fly ball to deep center field that nearly eluded Denard Span.

Lester also started Game 1 of the 2016 National League Championship Series against the Los Angeles Dodgers, he pitched six innings and allowed just one run and had a no-decision.

Lester was named the Game 1 starter of the 2016 World Series against the Cleveland Indians, where he took the loss after throwing 5.2 innings and allowing three runs.

[57] Lester was voted the Babe Ruth award as postseason MVP by the New York chapter of the Baseball Writers' Association of America.

[61] On July 1, 2018, Lester hit his 2nd career home run, a three-run shot, off of Lance Lynn in an 11–10 win over the Minnesota Twins.

On August 6, 2019, he called himself the "weakest link" in the Cubs rotation after giving up a career high 11 runs in a 11–4 loss to the Oakland Athletics.

[68] He earned his 200th career victory on September 20, 2021, against the Milwaukee Brewers, making him one of only three active pitchers (at that time) to achieve that mark.

On January 9, 2009, Lester married Farrah Stone Johnson,[73] who he met in 2007 while making rehab starts in single-A Greenville.

[76] During the season, they resided in the Graceland West neighborhood of Chicago in a $3.8 million home, but sold it in 2021 after Lester left the Cubs.

[78] Lester and his wife Farrah established NVRQT, short for "Never Quit", in 2011 to support children with cancer and researchers working towards a cure.