He began his acting career guest starring in the television shows Saved by the Bell: The New Class (1993), Touched by an Angel (1995), and Party of Five (1995).

Marsden left after one and a half years, opting instead to move to Los Angeles in order to pursue his acting career.

Singer had dropped out of the third X-Men film to direct Superman and Marsden was cast as Lois Lane's fiancé, Richard White.

Due to schedule conflicts, Marsden's screen time in X-Men: The Last Stand was reduced, stirring controversy from fans of the comics.

[8] In 2014 Marsden reprised his role of Cyclops in a brief cameo for X-Men: Days of Future Past, as did other actors from the first film including Anna Paquin and Famke Janssen.

Enchanted was well received critically and proved to be a commercial success, earning more than $340 million worldwide at the box office.

[10] Following his successes in 2007's Hairspray and Enchanted, Marsden played the male lead in the 2008 romantic comedy 27 Dresses opposite star Katherine Heigl, which grossed $160 million worldwide.

[15] In 2010, Marsden was cast in the comedy Death at a Funeral, a remake of the 2007 British film of the same name, along with Chris Rock, Luke Wilson, Danny Glover, and Columbus Short.

[16] In April, Marsden appeared as the male (live-action) lead in Hop, an Easter-themed comedy co-starring Russell Brand as the Easter Bunny.

[19][20] In 2012 and 2013, Marsden appeared in a recurring role in the sixth and seventh seasons of 30 Rock, playing Criss Chros, the boyfriend (and later husband) of the series' main character Liz Lemon.

In 2013, he co-starred with Denzel Washington and Mark Wahlberg in the action film 2 Guns, which debuted at number one in its weekend release.

Marsden played Jack Lime,a rival reporter to Will Ferrell's Ron Burgundy, in Anchorman 2: The Legend Continues.

Marsden appeared as Judy Hale's former boyfriend and lawyer Steve Wood in the Netflix dark comedy series Dead to Me.

[27][28] In 2023, Marsden starred as himself in the hoax reality television series Jury Duty, a role which garnered him a Golden Globe nomination.