Ryan is well known for his starring roles in the National Lampoon, movie Van Wilder and the American television series Two Guys, a Girl and a Pizza Place playing medical student Michael "Berg" Bergen. He also cameoed in Harold & Kumar Go to White Castle as a nurse, appeared in The In-Laws with Michael Douglas and Albert Brooks, and in 2003, the Canadian production Foolproof. In 2004, he co-starred in the action/horror film Blade: Trinity as Hannibal King, and in 2005 he played a waiter named Monty in Waiting.... He has also appeared in an episode of the television series Scrubs, where he played Spence, a college friend of J.D. and Turk.
Although he has performed primarily in comedies, Reynolds played the dark character George Lutz in the remake of the horror movie, The Amityville Horror. Reynolds also played the less comedic character of Hannibal King in the film Blade: Trinity, which also starred Wesley Snipes and Jessica Biel.
In a March 2005 interview, Reynolds spoke of his interest and involvement in a possible film adaptation of Deadpool (comics) with screenwriter David Goyer. Growing fan interest and having Avi Arad's son—a hardcore Deadpool fan—behind to project, increases the prospects of the film being made.