In July 2008, he joined Premier League club Aston Villa for a fee of $1 million, where he made 171 total appearances across eight seasons.

On August 1, 2008, Guzan was granted a work permit by the Home Office, allowing him to complete his move to Aston Villa.

He then helped Aston Villa overcome the Italians in the final, most notably in the penalty shootout during which he saved the attempts of Vincenzo Iaquinta and Alessandro Del Piero.

Despite having a successful pre-season period, Guzan was dropped from the first team in favor of Friedel for Aston Villa's opening game of the 2009–10 season against Wigan Athletic.

[14] On March 8, however, Hull re-signed Guzan on an emergency loan deal due to an injury to goalkeeper Vito Mannone.

[17] On December 3, 2011, Guzan made his second Premier League appearance for Aston Villa, coming on for the injured Shay Given against Manchester United.

[18] However, he was linked with a return to the club over the summer in a situation similar to that of fellow Aston Villa goalkeeper Andy Marshall in 2010.

On July 16, 2012, Guzan was included in new manager Paul Lambert's 25-man squad for Aston Villa's tour of the United States and on the same day, the player confirmed via Twitter that he had renewed his contract and rejoined the club.

[19][20] He made his return for Aston Villa against Newcastle United putting in a Man of the Match performance in a 1–1 draw at St James' Park.

[21] He kept Villa's first clean sheet of the season in a 2–0 win against Swansea City and performed well enough to keep his position in the starting lineup.

On July 29, 2016, Guzan signed a two-year contract with newly promoted Premier League club Middlesbrough, joining on a free transfer, after Aston Villa were relegated to the Championship.

[36] Guzan made his United States national team debut on February 19, 2006, in a friendly 4–0 win over Guatemala in Frisco, Texas.

[40] When the United States came runners-up at the 2009 FIFA Confederations Cup in South Africa, he played in a 3–0 group victory against Egypt that put the team into the semi-finals at the expense of their opponents and Italy.

[41] Guzan was unused at the 2010 FIFA World Cup[42] and played no international games between that November and May 2012, when he came on as a substitute for Tim Howard near the end of a 5–1 friendly win over Scotland in Jacksonville.

[44] At the 2015 CONCACAF Gold Cup, in which the United States came fourth, Guzan and Michael Bradley were the only two Americans to start every game;[45] he won the Golden Glove.

He played the first two group games before Bill Hamid took his place for the third, then he and Sean Johnson were replaced in the squad by Howard and Jesse González.