O'Quinn was born in Newberry, Michigan. He attended Central Michigan University in Mount Pleasant, Michigan, and the University of Iowa in Iowa City, Iowa. Before graduating, he worked as a security guard. O'Quinn has been married to his wife, Lori, for 25 years. Most of that time they lived in Finksburg, Maryland, but after Lost began airing, the couple decided to follow the example of O'Quinn's co-stars and move to Hawaii, where the series is shot. O'Quinn and his wife are the parents of two sons, Oliver and Hunter, who live on the West Coast of the United States.

O'Quinn began acting in the 1970s. He has appeared in such films as Tombstone, Heaven's Gate, The Rocketeer, and as the deranged serial killer in The Stepfather. His early television roles include guest appearances on Miami Vice (episode "Give a Little, Take a Little"), Earth 2, Moonlighting, Star Trek: The Next Generation (episode "The Pegasus"), The New Twilight Zone (episode "Chameleon"), Homicide: Life on the Street (episode "Hate Crimes"), and a recurring role as Rear Admiral Thomas Boone on JAG.

In 1995, O'Quinn began a series of notable guest appearances in The X-Files, Millennium, and Harsh Realm, all produced by Chris Carter, who also cast him in the film The X-Files: Fight The Future.

After a string of recurring appearances on Alias (2002–2003), as the FBI Director Kendall, O'Quinn became a favorite of television producer J.J. Abrams. Following a seven-episode guest run on The West Wing in 2003–2004, O'Quinn received a call from Abrams indicating that the producer wanted to cast him, with no audition needed, in his new television drama Lost[citation needed]. In 2005 and 2007, O'Quinn received an Emmy nomination for Best Supporting Actor in a Drama for his work as John Locke on Lost. O'Quinn admitted on the TV Guide Channel that he did not have much faith in the series Lost at first, calling it "The Mysterious Gilligan's Island of Dr. Moreau." On September 16, 2007, he won an Emmy Award for Outstanding Supporting Actor In A Drama Series for his role in Lost.

O'Quinn holds the distinction of having played four different characters within the extended X-Files / Millennium continuum (the two shows being classed together since both Lance Henriksen's character of Frank Black and Charles Nelson Reilly's character of Jose Chung have appeared in both shows) :

• Lt. Brian Tillman (1995) "Aubrey"
• SAC Darius Michaud (1998) X-Files: Fight the Future
• Unnamed Shadow man (2002) "Trust No 1", credited as Terrence Quinn.
• Peter Watts, a recurring character in seasons 1 through 3 of Millennium

• Was once a bodyguard
• Is good friends with 1013 Productions' Chris Carter, having appeared in most of his work: as a guest star in two episodes of "The X Files" (1993), a supporting role in The X Files (1998) and recurring roles on "Harsh Realm" (1999) and "Millennium" (1996/I).
• He was raised in Michigan.
• He elongated his last name to "O'Quinn" from his real name of "Quinn" to distinguish himself from another person named Terry Quinn already acting in films.
• He has been balding since his early 20s and has appeared with a partially or entirely shaved head in most of his films.
• Irish-American.
• Has been experienced in percussion since high school.
• Has had roles in both of J.J. Abrams' hit television series, "Alias" (2001) and "Lost" (2004).
• Not many know that he is a talented guitarist and singer. He is a particularly big Neil Young fan and can apparently do a dead-on impression of him.
• Although always friendly onset, he keeps private and mysterious habits apart from his younger "Lost" (2004) co-stars, who often get together for wild parties when not shooting. He keeps this enigmatic aura so they will regard him similarly to the way they regard his mysterious character Locke.
• He is one of the few cast members of "Lost" (2004) who did not have to audition, because his former collaborator (from "Alias" (2001)) J.J. Abrams thought of O'Quinn for the part of Locke before the actor was even offered it.
• Has 2 sons: Oliver (23 years) and Hunter (21 years)
• Graduated from the University of Iowa in Iowa City, Iowa.
• He graduated from Central Michigan University.
• Has appeared in episodes of two different television series with the same name. Both "Millennium" (1996/I) and "Lost" (2004) have had episodes featuring O'Quinn called "Walkabout".
• In an episode of "Lost" (2004), his character Locke's parents were played by Kevin Tighe and Swoosie Kurtz, who are both only eight years O'Quinn's senior.
• Has an Irish Terrier named 'Reggie'
• Was the chief architect for the infamous "Locke" baseball field designed mostly in part for the Three Village Little League.
• Actually learned how to properly throw and handle knives for his role on Lost.
• His brother, Thomas Anthony Quinn, is also an actor, who acts and teaches theatre in central Illinois.

"It looks like a camera on a stick." - when asked what the "monster" from "Lost" (2004) looks like. "I so rarely turned down a role, that I can't say I have any regrets in that regard. There were many roles that I would rather not have done, but having a home and family requires that we sometimes do things we would rather not. I have done a few roles that I've never watched, and if I happen to be flicking through channels and one pops up, I quickly move on. It's hard enough to sustain some self confidence without being reminded of things we'd rather not revisit but, in the end, it comes with the territory." "I don't think I could play a character that I couldn't relate to somehow. I'm not unfamiliar with frustration, anger, shame, helplessness and a load of other emotions that make up our psycho-soup. I try to focus on that frustration, that sense of unfairness, and multiply it." "I've told the producers that I miss the old John Locke. I wish he hadn't found those damn buttons sometimes. But these ups and downs reflect everybody's. You can't always choose the way things go. That's life."