He is known for his portrayal of Lieutenant Lynn "Buck" Compton in the HBO miniseries Band of Brothers (2001), Deputy District Attorney David McNorris on Boomtown (2002–2003), Tin Man in the Sci Fi Channel miniseries Tin Man, and as Dave Williams in Season 5 of Desperate Housewives (2008–2009), and President Dwight D. Eisenhower in American Horror Story: Double Feature (2021) for which he was critically acclaimed.

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 was set to star in the ABC dramedy Scoundrels,[7] but was fired for refusing to act in sex scenes, citing his family and Catholic faith as basis for his decision.

In 2012, McDonough had a recurring role in the third season of FX's Justified as Robert Quarles, a sadistic carpetbagging mobster from Detroit.

[10] During the 2014 Winter Olympics opening ceremony on NBC, McDonough was featured in a high-profile and frequently aired Poolside commercial for the Cadillac ELR hybrid electric car.

[12] In 2021, he was cast as President Dwight D. Eisenhower on the tenth season of American Horror Story, titled Double Feature.

[14] Throughout his career McDonough, has enjoyed recognition for his various character roles in both film and television, as well as for his voice work in animation and video games.

[16] In 2003, McDonough married Ruvé Robertson, a South African model whom he met in the United Kingdom while filming Band of Brothers.