Guzan had an impressive rookie campaign, starting all 18 matches in his first season at South Carolina. He finished the year with a 0.96 goals against average that was aided by eight shutouts; tied for the sixth-most in a season in school history. He was named to College Soccer News' All-Freshman team and was one of just two freshmen named to the NSCAA All-South team. He recorded 69 saves on the year, finishing with a 9-7-2 record.
Guzan has played for the Under-18 United States national team. He got his first cap for the senior national team on February 19, 2006, against Guatemala. On November 7, 2007, Guzan was named MLS Goalkeeper of the Year.
On July 11, 2008, Aston Villa agreed a transfer fee in the region of £600K or $1.2M with Major League Soccer and Chivas USA to sign Guzan, significantly less than the £2M agreed in Aston Villa's failed move for the keeper in January 2008. This was because Guzan would have been out of his contract at the end of the 2008 season in November, allowing him to sign for Aston Villa during the January transfer window on a free transfer.
On August 1, 2008, Guzan was granted a work permit by the Home Office, allowing him to complete his move to Aston Villa. He was due to be officially introduced by Aston Villa after competing for the United States at the 2008 Summer Olympics in Beijing, China. Guzan was the second American 'keeper signed during the summer by Villa, following the capture of Premier League veteran Brad Friedel.