Zegers was born in Woodstock, Ontario. He began his performing career at the age of six, appearing in commercials. His first film appearance was at the age of seven, in a small role in the Michael J. Fox comedy Life With Mikey (1993). Subsequently, he appeared in many supporting roles, including a guest appearance on the television series The X-Files, playing a stigmatic child. He had the starring role in Air Bud (1997), a film about a sports-playing dog. In the years following, Zegers appeared in three sequels, as well as a similar genre film, MVP: Most Valuable Primate (2000), which featured a hockey-playing chimp.
Between 1997 and 2004, Zegers had starring or co-starring roles in many low-budget Canadian and horror films, including Nico the Unicorn (1998), Komodo (1999), and Wrong Turn (2003). He also appeared in the short-lived American television series Titans (2000), for which he was personally chosen by producer Aaron Spelling. Zegers had previously worked with co-star Yasmine Bleeth in the 1999 film It Came From the Sky.
After appearing in the remake of Dawn of the Dead, he had a major role in the Academy Award-nominated independent film Transamerica (2005), costarring Felicity Huffman. Zegers' performance as the street hustling bisexual son of a male-to-female transsexual was praised by several critics, and he won the 2006 Cannes Film Festival Chopard Award, which is given to promising young actors. Zegers starred alongside Samaire Armstrong in the 2006 romantic comedy It's a Boy Girl Thing. In 2009, Zegers signed to play the role of Clyde Barrow in the remake of The Story of Bonnie and Clyde, alongside Hilary Duff. He also guest-starred in Gossip Girl from 2009 until 2010 and returning again in late 2010 for multiple episodes throughout season 4. He also appears alongside Miley Cyrus on Rock Mafia's new music video "The Big Bang".