Christopher McDonald was born and raised in New York City, New York, to Patricia, a real estate agent, and James R. McDonald, an educator. His breakout role was in Ridley Scott's Thelma & Louise (1991), followed shortly by his role as Jack Barry in Robert Redford's Quiz Show (1994). Other notable performances include Into Thin Air: Death on Everest (1997) as Jon Krakauer and Requiem for a Dream (2000) as Tappy Tibbons (opposite Oscar winner Ellen Burstyn). He co-starred in Happy Gilmore (1996), American Pie Presents: The Naked Mile (2006), American Pie Presents: Beta House (2007), Flubber (1997), and Leave It to Beaver (1997). His television credits include Harry's Law (2011), Boardwalk Empire (2010), and Family Law (1999).

Trained by legendary acting teacher Stella Adler and at the Royal Academy of Dramatic Art, McDonald was singled out by the New York Times as one of the most prolific actors in Hollywood. He has performed in over 100 films over more than four decades. His roughly 40 stage credits include Billy Flynn in the long-running Broadway reboot of Chicago and the 2013 hit Lucky Guy (opposite Oscar winner Tom Hanks).

Since the loss of two siblings and a parent to cancer, he has been an active supporter of the Make a Wish foundation along with charities which help cancer research. He participates in celebrity fund-raising events throughout the world. A graduate of Hobart and William Smith college in 1977, he is the principal donor for the building of the school's new Performing Arts Center.