At John F. Kennedy High School in Granada Hills, California, Garland won All-State Player of the Year twice, and won 1st team High School All-American honors once.

Garland was selected by the Chicago Cubs with the 10th pick of the 1997 Major League Baseball Draft and pitched in 10 games for the Arizona League Cubs with a 3-2 record and a 2.70 ERA to finish the season. He began 1998 with the Single-A Rockford Cubbies, but was traded to the Chicago White Sox just before the trade deadline for relief pitcher Matt Karchner who had previous success in the majors, but was having a down season with the White Sox (5.15 ERA). Unfortunately for the Cubs, Karchner didn't fare any better with them that season (5.14 ERA) and was released in 2000 while Garland dominated the minor leagues on his way to securing a spot in the White Sox's rotation for seven seasons.

Garland started 1999 with High-A Winston-Salem and after 19 starts and a 3.33 ERA, Garland was promoted to Double-A Birmingham. In 2000, he was the White Sox's #2 prospect and went 9-2 with a 2.26 ERA for Triple-A Charlotte before earning a promotion to the major leagues. For his success in Triple-A, Garland was voted a Triple-A All-Star and International League All-Star and to Baseball America's 2nd team Minor League All-Star team and the International League Most Valuable Pitcher. He started 2001 with Charlotte again, but was back in the majors after only 5 starts.

Garland made his major league debut as the youngest player in the American League at age 20 on July 4, 2000, against the Kansas City Royals, but gave up 7 earned runs before being chased from the game after 3 innings. In 15 games in 2000, all but 2 of them starts, he had a 4-8 record and a 6.46 ERA. In 2001, Garland started in the minors, but was called up and made his first appearance of the year on May 2. Garland spent the rest of the year mixing his time between the bullpen and rotation.

In 2002, he became a full-time starter and posted average seasons the next three years. In 2002, he was 12-12 with a 4.58 ERA, in 2003, he was 12-13 with a 4.51 ERA, and in 2004, he was 12-11 with a 4.89 ERA. Garland's 2005 season was very strong; he went 18-10 with a 3.50 ERA, 115 strikeouts, and led the AL with 3 shutouts. He also made the All-Star Team, pitching 1 scoreless inning, and helped the White Sox win the American League Central Division and the 2005 World Series. In Garland's first career postseason start, he threw a complete game, 4-hitter, with 7 strikeouts against the Los Angeles Angels of Anaheim, in the ALCS. In his other postseason start, in the World Series, Garland pitched 7 innings and gave up only 2 earned runs.

Following the 2005 season, Garland signed a three-year $29 million contract, avoiding salary arbitration. 2006 was similar to his seasons before 2005. Despite having a 4.51 ERA, he went 18-7 and his 46 combined wins from 2004 to 2006 were tied for the sixth most in the majors over that period. He also hit his first major league home run on June 18, 2006, off Cincinnati Reds pitcher Esteban Yan. During the 2006 offseason, Garland was nearly traded to the Houston Astros for Taylor Buchholz, Willy Taveras, and Jason Hirsh. The trade fell apart after White Sox general manager Kenny Williams became concerned with the health of Buchholz.

After another average season in 2007, Garland was traded on November 19, 2007, to the Los Angeles Angels of Anaheim for shortstop Orlando Cabrera. The Angels, who had depth at shortstop, liked Garland's durability and he didn't disappoint in 2008; he extended his streak of at least 32 games started to 7 consecutive seasons.

On January 29, 2009, Garland signed a one-year deal with the Arizona Diamondbacks with an option for 2010. He was 8-11 with a 4.29 ERA in 27 starts for the Diamondbacks.

Garland was traded to the Los Angeles Dodgers on August 31, 2009 for a player to be named later (Tony Abreu). He was already in Los Angeles as the Diamondbacks were playing the Dodgers that day. Television camera showed Garland being told of the trade during the sixth inning. He made his Dodgers debut on September 3, 2009 pitching against his old teammates. During this game, the Diamondbacks broadcasters found their key of the game from a 9th grader which was, "Keep your friends close, keep Jon Garland closer." He pitched in six games for the Dodgers, finishing 2-3 with a 2.72 ERA but was left off the post-season roster. After the season, the Dodgers declined the $10 million option on Garland for the 2010 season, making him a free agent.

On January 26, 2010, Garland agreed to a one-year deal with the San Diego Padres. Jon Garland recorded the 1000th strikeout of his career on May 30, 2010 which helped beat the Nationals 3-2 in extra innings.