In 2002, he joined newly promoted Hannover 96, becoming only the third Canadian to play in the German First Bundesliga. He made 20 appearances during 2002–03 season and 32 appearances in both 2003–04 and 2004–05 seasons.

De Guzman’s contract with Hannover expired in 2005 allowing him to move to any team with no transfer fee. He was heavily linked with a move to Tottenham where he would have joined Canadian captain Paul Stalteri. He decided against the move to London due to the depth in the centre of mid-field, and instead chose to join Deportivo La Coruña in Spain becoming the first Canadian to play in La Liga. After playing a starring role in the club’s remarkable turnaround in the 2007–2008 season to avoid relegation and gain a spot in the UEFA Cup, de Guzman was named the team’s player of the season. In 95 appearances he scored one goal. His only goal with Deportivo came in 2005 against the Spanish giants Real Madrid. His contract with Deportivo expired in the summer of 2009.

In September 2009 an agreement was reached with Toronto FC for de Guzman to sign as a designated player, becoming the first ever Canadian Designated Player in league history. His contract was worth $1,910,746 annually. The Canadian midfielder signed a three-year deal to play in MLS. De Guzman made his debut for the club in an away game against the Los Angeles Galaxy on September 19, 2009. He finished the 2009 season with five appearances. De Guzman was able to convince former Deportivo teammate and friend Mista to join Toronto in July 2010. De Guzman was heavily criticized for his inconsistent performances as a designated player in the 2010 season making 36 appearances in all competitions. Much doubt was left over the future of de Guzman and Toronto on November 23 when the club failed to protect him for the 2010 MLS Expansion Draft, meaning Vancouver Whitecaps FC or Portland Timbers could select him if they were willing to take on a Designated Players Salary. However, he was untouched going through the sixth round when Vancouver selected O’Brian White which allowed Toronto to protect one player for the remaining four rounds in which they protected de Guzman . On January 5, 2011, de Guzman revealed that he would be undergoing knee surgery to repair a torn meniscus which might have plagued his performance for the last quarter of the season.

In January 2011, Toronto hired Aron Winter as the head coach of the club to bring in a new style of possession soccer, many pundits believed that this new style would benefit de Guzman’s abilities and allow him to succeed within the MLS. Ten days before the new season kicked off it was revealed that de Guzman would miss this first game against Vancouver and potentially a few more, due to Winter not wanting to aggravate the recent successful surgery. De Guzman scored his first goal for Toronto in CONCACAF Champions League play against Tauro FC August 18, 2011, the game ended in a 2–0 away victory.

On June 1, 2011, in a friendly against Ecuador in the last minutes of play Canada was down 2–1 when de Guzman played a clever yet controversial quick free kick just outside the 18 yard box to Tosaint Ricketts who put in the net for his first ever international goal leading the Canadian team to a well earned draw. De Guzman earned his fiftieth cap for Canada’s senior men’s team on October 7, 2011, in a dominating 7–0 victory over Saint Lucia in a 2014 FIFA World Cup qualification match at Beausejour Stadium.

On July 13, 2012, de Guzman was traded to FC Dallas in exchange for forward Andrew Wiedeman. De Guzman made his debut for Dallas against San Jose Earthquakes on July 18, the game ended in a 2–1 away defeat. De Guzman scored his only goal for Dallas on September 15 against Vancouver, a left footed volley more than 20 yards out six minutes into second half stoppage time.

De Guzman remained with FC Dallas through the 2012 season. His contract expired after 2012 and the club made him available for the 2012 MLS Re-Entry Draft in December 2012. de Guzman became a free agent after he went undrafted in both rounds of the draft.

Following the 2013 CONCACAF Gold Cup in late July, de Guzman signed for Skoda Xanthi in the Superleague Greece. His debut came in a third round UEFA Europa League match against Standard Liège on August 1. He scored in the second leg of the series on August 8, but Skoda Xanthi would lose 4–2 on aggregate. He made his league debut for the club on August 17 in a 3–0 loss to P.A.O.K.. After his contract expired, he looked for a club in or near Germany to be closer to his family, but he has not found anything as of yet.

After several months without a club he was rumoured to be signing with Columbus Crew following a training spell with the MLS club, however a week later de Guzman signed with Ottawa Fury of the North American Soccer League on March 27, 2015. He made his debut on April 4 against the Carolina RailHawks.

On December 16, 2015, de Guzman re-signed with Ottawa for the 2016 season. He was subsequently named captain of the club on March 9, 2016.

On November 17, 2015, de Guzman started for Canada against El Salvador in a 2018 World Cup qualifying match and overtook Paul Stalteri as Canada’s most capped player in history earning his 85th cap.

On January 30, 2017, de Guzman announced his retirement from soccer and his transition to an assistant coaching position with the Ottawa Fury. On August 15, 2017, de Guzman was named interim head coach until the end of the 2017 season after the resignation of head coach Paul Dalglish.

On December 21, 2017, de Guzman was appointed general manager of the Ottawa Fury, alongside new head coach Nikola Popovic. He held the role until the Fury ceased operations at the end of 2019, following not receiving sanctioning to play in the US-based USL Championship.

In 2020, it was announced that he was joining the newly formed club 1812 FC Barrie, where he will serve as president and co-owner.