Schmidt made his professional debut with the Gulf Coast Braves in 1991, starting eleven games and finishing with a 3–4 record and 2.38 ERA.

In 1996 he started the season in the Braves rotation but also spent time in Richmond and on the disabled list before he was traded to the Pittsburgh Pirates (with Ron Wright) for Denny Neagle on August 30, 1996.

Schmidt was then acquired by the Giants in 2001 with John Vander Wal in exchange for Armando Ríos and Ryan Vogelsong.

Schmidt threw a 2–0 shutout in Game 1 of the 2003 NLDS, beating Josh Beckett, but his team lost once again in the playoffs, this time to the Florida Marlins.

He also set a San Francisco single-season record of 251 strikeouts, which was broken when Tim Lincecum struck out 265 in 2008.

On June 6, 2006 at AT&T Park, in a 2–1 win over the Florida Marlins, Schmidt pitched a complete game and struck out a career-high 16 batters.

Schmidt struck out the final three batters of the game, starting with cleanup hitter Miguel Cabrera, Josh Willingham and Jeremy Hermida.

Not only did he tie the franchise all-time single-game strikeouts record originally set by Christy Mathewson of the New York Giants on October 3, 1904, against the St. Louis Cardinals, but he also surpassed Gaylord Perry's San Francisco Giants single-game strikeouts record, when Perry struck out 15 batters on July 22, 1966, against the Philadelphia Phillies.

Heading into 2009, Schmidt was expected to compete for a spot in the Dodgers' rotation but pitched poorly in spring training and began the season once more on the disabled list.

[3] He made another start on July 26 against the Florida Marlins, but pitched poorly and allowed five runs (four earned) in three innings and was credited with the loss.