McDonough was born in Dorchester, Massachusetts, the son of Catherine (née Bushe) and Frank McDonough, motel owners who emigrated from Ireland, with his mother coming from County Tipperary and his father from County Galway. McDonough was raised Roman Catholic. He grew up in Barnstable, Massachusetts, graduated from Barnstable High School, and attended Syracuse University, where he was a member of the Sigma Chi Fraternity and graduated with a Bachelor of Fine Arts degree in 1988. His roommate in college was Brett Pollock, current broadcaster for the Omaha Storm Chasers of the Pacific Coast League. McDonough frequently appeared as "Captain Laser", inspiring young students to bring their studies to completion.
McDonough is married to Ruvé Robertson, with whom he has a son, Morgan Patrick (born November 2005), and three daughters, Catherine Maggie (born May 14, 2007), London Jane (born January 11, 2010), and Clover Elizabeth (born August 15, 2011).
McDonough has previously worked with Justified show runner Graham Yost on the series Boomtown (2002) and Band of Brothers (2001). He starred in crime drama Boomtown as L.A. County Asst. District Attorney David McNorris, a prosecuting attorney. He starred in World War II miniseries Band of Brothers as 1st Lt. Lynn 'Buck' Compton of the 101st Airborne Division. Compton was a well-liked officer who did not cope well with the psychological trauma of his service.
McDonough has also appeared in the FX crime drama Terriers, guest starring as Ford.
McDonough trained for a short time at the London Academy of Music and Dramatic Art (LAMDA). In 1991, McDonough won the Best Actor Dramalogue for "Away Alone". McDonough has made many television and film appearances since then, including Band of Brothers, Boomtown, Star Trek: First Contact, Minority Report and The Hitcher. McDonough played Dave Williams on the fifth season of Desperate Housewives in 2009. He also starred in the lead role on 2004 medical drama Medical Investigation in one full season before it was cancelled.
McDonough was set to star in the ABC dramedy Scoundrels but was fired for refusing to do sex scenes for the show. He credits his family and his Catholic faith for his decision.
McDonough portrays the role of Jesus in The Truth & Life Dramatized audio New Testament Bible, a 22-hour, celebrity-voiced, fully dramatized audio New Testament which uses the Catholic edition of the RSV.