Bierko is perhaps best known for his role as Timothy in the 1996 action film The Long Kiss Goodnight, as Max Baer in the film Cinderella Man, as Tom Ryan in Scary Movie 4 (spoofing Tom Cruise throughout the film) and on the Broadway stage as Harold Hill in The Music Man. He was also the original choice for the character of Chandler Bing on the sitcom Friends but turned it down. He had a short role as attorney Jeffrey Coho during the third season of the ABC television series Boston Legal.
Bierko was born in Rye Brook, New York to Rex and Pat Bierko; his mother was Jewish, but converted to Catholicism, raising Bierko Catholic. Bierko studied journalism at Boston University and studied at the School of Speech at Northwestern University (graduating in 1986).
Bierko has been involved with a number of actresses, such as Charlize Theron, Gretchen Mol (with whom he co-starred in the movie The 13th Floor), Janeane Garofalo, and Meg Ryan.