He played in Major League Baseball (MLB) from 1999 to 2013 for the Montreal Expos, New York Yankees, Oakland Athletics, Toronto Blue Jays, Chicago Cubs and Los Angeles Dodgers.

After two seasons in the Dodgers farm system, he was traded (along with Peter Bergeron, Wilton Guerrero and Jonathan Tucker) to the Montreal Expos for Hiram Bocachica, Mark Grudzielanek and Carlos Pérez.

[5] Lilly played for more than two years with the Yankees before being dealt to the Oakland Athletics in a three-team deal that included pitchers Jeff Weaver heading to New York and Jeremy Bonderman going to the Detroit Tigers.

On the morning of December 6, 2006, he informed the Blue Jays that he would not be returning to the club, thus rejecting a four-year, $40 million deal.

Later on that day, Lilly agreed to an identical four-year, $40 million deal with the Chicago Cubs, officially ending his tenure with the Blue Jays.

[16] Lilly pitched well in April, lasting at least six innings in each of his five starts while never giving up more than three runs in a game posting a 2.18 ERA.

In game one of the series, Alfonso Soriano hit three home runs in his first three at-bats as part of a Cubs 9–1 victory.

[19] On the final game of the series, Lilly hit Édgar Rentería in the first inning, and was promptly thrown out of the ballgame by Jim Wolf.

In the ninth, he gave up a lead off single to Juan Pierre, then was lifted for relief pitcher Carlos Mármol, who got the save, getting out of a bases loaded jam, for a 1-0 Cub victory.

[25] His second start was against Puerto Rico, a game that Team USA would win with a David Wright two-run single in the bottom of the ninth.

On July 31, 2010, Lilly and Ryan Theriot were traded to the Los Angeles Dodgers for Blake DeWitt, Brett Wallach, and Kyle Smit.

He finished his season with the Dodgers with a record of 7-4 and a 3.52 ERA in 12 starts, which included a complete game shutout on August 19 against the Colorado Rockies.

[32] Lilly returned for spring training in 2013 but lost time due to illness and rainouts so he was unable to build up arm strength.

[34] After injuries to starters Zack Greinke and Chris Capuano, Lilly was activated off the disabled list and returned to the rotation on April 24.

[42] On August 6, 2013, Just a few days after being released by the Dodgers, reports claimed Lilly was signed to a minor league contract by the San Francisco Giants.

He also demonstrated the ability to throw a variety of pitches: a changeup, two fastballs—a four-seamer and a two-seamer in the 86-90 mph range, as well as two breaking balls, a slider and a curveball.

[55] He accepted a plea bargain to pay a $2,500 fine, be on informal probation for two years, and perform 250 hours of community service.