Itzin was born in Washington, D.C., the son of Evelyn Loretta (née Smith) and Martin Joseph Itzin. When he was in sixth grade, his family moved to Burlington, Wisconsin, where his father was mayor. Itzin originally intended to become a theater actor, receiving training at the American Conservatory Theater in San Francisco. He has appeared on many stages across the country.
Itzin has appeared in guest starring roles on various television shows like in "MacGyver" Final Approach (TV Episode 1986). His most recent major role has been President Charles Logan on the popular television drama 24. He received a Tony Award nomination for his role in the Pulitzer Prize–winning play The Kentucky Cycle. In the movie Airplane!, Itzin plays Religious Zealot #1, and has the first lines in the movie, but disappears after the first scene. He had a short role in The A-Team episode 'Wheel of Fortune', as accountant Howard for a casino-owner.
In 2005, Itzin joined the cast of 24, halfway through its fourth season, in the recurring role as Vice President Charles Logan. By the following season the character had become President and was expanded to become one of the leading figures in the storyline. Itzin received an Emmy nomination for Outstanding Supporting Actor in a Drama Series for this performance. He didn't have to audition for the role, since he had previously auditioned for a role during the second season of the show, and knew one of the producers. Itzin returned for four episodes in season six. Itzin returned for a story arc during the eighth season of the show to help President Allison Taylor keep the Peace Treaty alive. This resulted in an Emmy nomination for Outstanding Guest Actor in a Drama Series. Somewhat coincidentally, before this role, Itzin played a Presidential Candidate in a commercial for cheese products, who was deemed a "doofus" for not liking cheese.
In 2007, he made a guest appearance as William Adama, Dick Tracy, and a police officer at Randy's Halloween night in an episode of Robot Chicken.
Itzin has held recurring roles on popular TV series such as Friends as Theodore Hannigan, father of Mike Hannigan, Murder One, NCIS, and The Mentalist. He played the head of the unit in the latter for 13 episodes, before leaving to return to 24 for its final season. Itzin also appeared on Night Court, Matlock, Diagnosis: Murder, Jake and The Fatman, The O.C., "Beverly Hills, 90210", Judging Amy, Boston Legal, CSI: Crime Scene Investigation, The Practice, The Pretender and the short-lived science fiction series, Firefly. He also portrayed John Ashcroft in the 2003 television movie DC 9/11: Time of Crisis. He currently has a recurring role on Covert Affairs.
He is also a frequent Star Trek actor, having played five different roles in the various series over the years; his most recent Trek role was Admiral Black in Star Trek: Enterprise. He made his first Star Trek appearance in 1993, in the Star Trek: Deep Space Nine episode "Dax". He later guest starred on DS9 again, in the sixth-season episode "Who Mourns for Morn?". He also appeared as Doctor Dysek in the episode "Critical Care" in the 7th season of Star Trek: Voyager.
He also starred in Fear and Loathing in Las Vegas as a Mint Hotel clerk, who looked and sounded a lot like actor McLean Stevenson on M*A*S*H. He played a psychiatrist in the Lindsay Lohan thriller I Know Who Killed Me and, most recently, as a prison warden in Law Abiding Citizen.
On stage, he has appeared in numerous theatrical venues across the country, and is a member of the Matrix Theatre Company in Los Angeles, where he has acted in award-winning productions of Waiting for Godot, The Homecoming, and The Birthday Party (each earning him an L.A. Drama Critics Circle Award for performance). For his work in the Pulitzer Prize-winning The Kentucky Cycle (which he performed in the world premiere at the Intiman Theatre, Mark Taper Forum, the Kennedy Center, and on Broadway), he received Tony Award and Drama Desk nominations.
He recently appeared on stage as Louis de Rougemont in the world premiere of Donald Margulies Shipwrecked! An Entertainment at South Coast Repertory, and subsequently revived at the Geffen Playhouse.
Itzin was a special guest star on the Disney Channel hit show Hannah Montana in the season two episode "Test Of My Love" as a billionaire whose son becomes a romantic interest of Miley's.
He hosted ACME: This Week! at the ACME Comedy Theatre on February 23, 2008 appearing in several sketches as well as a short film, "Law and Order: Really Special Victims Unit".
He has played in several radio plays with The L.A. Theatre Works, and most recently played the Archbishop in the Hollywood Theater of the Ear's 2010 audio production of Saint Joan.
He had a recurring role in seasons 1-4 of USA Network's series, Covert Affairs.
In 2010, Itzin starred as Kenneth Lay in Broadway production of the play Enron
In 2010, he appeared as the Earl of Kent in the Antaeus Company's production of King Lear. He won the L.A. Drama Critics Circle Award for this performance.
In 2010 - 2011, Itzin appeared in several episodes of Desperate Housewives (season 7) as a patient in a dialysis clinic.
In 2011, he appeared in The Ides of March as former Senator Jack Stearns, father of Molly Stearns and the chairman of the Democratic National Committee.
In 2012, Itzin played John Archibald Campbell in the movie Lincoln.
In 2013, Itzin made a guest appearance as the father of Victor Frankenstein on the twelfth episode of the second season of Once Upon a Time, "In the Name of the Brother".
In 2015, Itzin appeared as Alex Mackey on Episode 12 of Season 5 of Hawaii Five-0, a police procedural series aired on CBS in 2015. Alex was a former employee at a local reformatory, in which four young boys disappeared in 1974, and turned out that he was the bad guy of the story.