Webb pitched in Major League Baseball (MLB) for the Arizona Diamondbacks from 2003 through 2009, and, after multiple shoulder surgeries, signed with but did not play for the Texas Rangers in 2011.

After the season he signed a four-year contract extension worth a guaranteed $19.5 million (that included a team option for 2010).

[7] An early contender to win the National League Cy Young Award, Webb pitched in the 2006 MLB All-Star Game, recording one hitless inning.

He scored a win in an emotional outing versus the San Diego Padres on August 28, pitching seven effective innings.

The win came a day after close friend and former UK teammate Jon Hooker and his new bride were among the victims of the doomed Comair Flight 5191 leaving Lexington.

[8] Webb went on to finish the 2006 season with a record of 16–8 and an earned run average of 3.10, and was recognized with the NL Cy Young Award.

Webb's win total marked the lowest for a starting pitcher who won the Cy Young in a full season.

In 2007 Webb logged a then-franchise record 42 scoreless innings streak as of the conclusion of his start on August 17, 2007, including three straight shutouts.

Webb carried the D'backs rotation in 2007, leading the team as it won the National League West crown.

Webb began the 2008 season with nine straight wins, becoming the first Major League pitcher to do so since Andy Hawkins won his first ten in 1985.

Webb became a free agent at the conclusion of the season and on December 26, 2010, agreed to a one-year contract with the Texas Rangers.

On July 24, the Rangers announced Webb would undergo a second right rotator cuff surgery on August 1, 2011, that would sideline him until the start of the 2012 season.

[20][21] In May 2013, he filed a workers' compensation claim against the Texas Rangers for shoulder, neck, back, arm, and musculo-skeletal system injuries.