At the age of 15, he asked his mother to take him into New York City to get an agent and try his hand in professional acting. He made his professional debut off-Broadway at age 16 in 1993 in the New York premiere of Edward Albee’s play Finding the Sun with the Signature Theatre Company. He played the role of “Fergus”. Both he and the production, which was also directed by Albee, received positive reviews. A decade later, in 2003, he appeared again off-Broadway, briefly, in the play Rain Dance.

In early 1997, Van Der Beek auditioned for three television pilots. One of them was for the fledgling WB Network show Dawson’s Creek. Van Der Beek won the title role of Dawson Leery, and the show’s 1998 debut was a success that helped to establish the network and its cast. The series ran for six seasons and was syndicated worldwide. In 1999, he starred in the teen football drama Varsity Blues, which held the number 1 spot at the U.S. box office for its first two weeks. He won an MTV Movie Award for his role.

He attended Drew University, on an academic scholarship, where he participated in an all-male a cappella group, but dropped out to pursue acting. He performed at the Vineyard Theater in New York in Nicky Silver’s play, My Marriage to Ernest Borgnine, and he played a supporting role in the independent film Cash Crop, which was originally shot in spring of 1997 and originally titled Harvest until released in 2001.

Around this time he was selected one of People magazine’s “50 Most Beautiful People in the World”, and he appeared in several other films, including Texas Rangers, Scary Movie, and Jay & Silent Bob Strike Back, playing himself playing Jay in the film within the film opposite Jason Biggs as Silent Bob. In 2002, he played Sean Bateman (younger brother of American Psycho protagonist Patrick Bateman) in the film adaptation of the novel The Rules of Attraction by Bret Easton Ellis., written and directed by Roger Avary. The film was an initial box office failure, but found a cult following on DVD.

In 2006, he appeared on the Direct-to-DVD thriller The Plague, which was produced by Clive Barker and was panned by critics. After Dawson’s Creek ended in 2003, he returned to off-Broadway, in Lanford Wilson’s Rain Dance. He completed an unproduced screenplay titled Winning. Since then, he made a few appearances on television, including a role on Ugly Betty. In 2007, he guest-starred in a two-part episode of the series Criminal Minds, playing a serial killer with dissociative identity disorder called Tobias Hankel who kidnaps and drugs one of the main characters, Spencer Reid. In 2008, he made a guest appearance on How I Met Your Mother, in which he played Simon, one of Robin Scherbatsky’s early boyfriends, multiple times.

In 2008, he began a recurring role on One Tree Hill as a filmmaker who was largely the satirical opposite of Dawson Leery. He appeared in an episode of the fifth season of Medium. In 2009, he portrayed real life kidnapper Anthony Steven “Tony Zappa” Wright in the Lifetime network television film Taken In Broad Daylight. In 2009, he won Best Actor at the 8th Annual San Diego Film Festival for his portrayal of FBI agent Jake Kelly working in Taiwan in the political thriller Formosa Betrayed, which also won Best Picture. The film was distributed theatrically in the United States starting February 26, 2010.

Van Der Beek was previously married to actress Heather McComb from 2003 until their separation in April 2009. Van Der Beek filed for divorce in the fall of that year, which was finalized and enforced in spring 2010.

On January 5, 2010, TVGuide.com confirmed that Van Der Beek had been cast in a major recurring role on the television series Mercy. He played Dr. Joe Briggs, the new womanizing ICU chief who harbors a dark secret. He starred alongside Rhona Mitra, Josh Lucas, and Jon Hamm in the Anders Anderson thriller film Stolen.

Van Der Beek married business consultant Kimberly Brook on August 1, 2010, in a small ceremony at the Kabbalah Center near Dizengoff Plaza in Tel Aviv, Israel. The couple have five children, Olivia (born September 25, 2010), Joshua (born March 13, 2012), Annabel (born January 25, 2014), Emilia (born March 23, 2016), and Gwendolyn (born June 15, 2018). They announced in October 2019 that they were expecting their sixth child. In November 2019, it was revealed that Van der Beek’s wife, Kimberly, had suffered a miscarriage. In September 2020, they announced that they were leaving Los Angeles and moving to Texas.

In 2011, he portrayed Kesha’s nemesis in her music video for “Blow”. He portrayed a fictionalized version of himself on the television series Don’t Trust the B—- in Apartment 23. The show debuted to critical praise, with Van Der Beek earning particularly good notices for his comic timing and sendup of his own image. The show was cancelled after two seasons, but remains popular on Netflix and on Logo TV which picked it up in syndication.

On March 4, 2015, he began his role as Senior Field Agent Elijah Mundo on CSI: Cyber. In 2017, Van Der Beek appeared in the British comedy series Carters Get Rich. Van Der Beek is also the co-creator and star of What Would Diplo Do?, in which he portrays producer and DJ Diplo. He made a cameo in the film Downsizing (2017), starring Matt Damon, and voices Boris Hauntley in the Disney Junior show Vampirina.