Thinnes was born in Chicago and educated at Los Angeles City College. His ethnic background is German. His first primetime role was as a brother of ex-cop Lee Marvin in a 1962 episode of The Untouchables, called "A Fist of Five". Later he appeared as Ben Quick in the short-lived 1965-66 television series The Long Hot Summer, which ran on ABC. During its run he received around 1,500 letters a week from women and appeared on the cover of TV Guide (April 9–15, 1966 issue) for his one and only time to date. The TV series The Invaders soon followed, with Thinnes playing an architect named David Vincent who accidentally witnesses the arrival of aliens from another planet and wages a seemingly hopeless one-man campaign against them. The series became a cult classic, leading to other 'aliens vs earthlings' films and TV shows.
Another short-lived series in which Thinnes starred was in the lead role on The Psychiatrist as Dr. James Whitman. In 1963, Thinnes guest starred as David Dunlear in the episode "Something Crazy's Going On in the Back Room" of The Eleventh Hour. In 1964, he appeared twice in episodes "Murder by Scandal" and the "Lost Lady Blues" of the 13-episode CBS drama The Reporter starring Harry Guardino as journalist Danny Taylor of the fictitious New York Globe newspaper. Thinnes also appeared as a guest star on Twelve O'Clock High, becoming a casualty of war while commanding a B-17 on a dangerous mission. He appeared as intrepid writer and investigator of the supernatural David Norliss in 1973's The Norliss Tapes, a pilot for an unproduced TV series, and played a suspicious schoolmaster in the TV movie Satan's School for Girls.
He appeared in the disaster films Airport 1975 as the co-pilot, and The Hindenburg as a sadistic SS captain. Thinnes was cast in Alfred Hitchcock's 1976 film Family Plot in the role of nefarious jeweler Arthur Adamson when Hitchcock's first choice, William Devane, was unavailable. Thinnes had already shot several scenes for the film when Devane suddenly became available. Hitchcock fired Thinnes and re-shot all of his scenes. He confronted Hitchcock in a restaurant and asked the director why he was fired. Flabbergasted, Hitchcock simply looked at Thinnes until the actor left. Some shots of Thinnes as the character (from behind) remain in the film.
During the 1982-1983 season, Thinnes appeared as Nick Hogan in 35 episodes of Falcon Crest. He later played Roger Collins in the 1991 revival of TV's Dark Shadows. He appeared on General Hospital as Phil Brewer from 1963-65, and in the 1979 miniseries From Here to Eternity. He appeared on One Life to Live as Alex Crown from 1984-85, and as Sloan Carpenter from 1992-95. He also played a lead role in "The Final Chapter," the first episode of the 1977 series Quinn Martin's Tales of the Unexpected (known in the United Kingdom as Twist in the Tale), and in "The Crystal Scarab", a first-season episode of Poltergeist: The Legacy in 1996. Thinnes was once considered by Paramount for the part of Captain Jean-Luc Picard in Star Trek: The Next Generation.
He also appeared in the 1988 pilot episode of Law & Order, "Everybody's Favorite Bagman", as District Attorney Alfred Wentworth. By the time the show was picked up in 1990, however, Thinnes was contractually obligated to another TV series, and so his character was replaced with D.A. Adam Schiff, played by Steven Hill. Thinnes made two appearances in The X-Files as Jeremiah Smith, an alien rebel with healing and shape-shifting abilities.
Thinnes also appeared in the 1995 TV mini-series The Invaders starring Scott Bakula, in which he returned as a much older David Vincent. Thinnes twice appeared on the ABC soap opera One Life to Live playing two different characters. From 1984-1985, he played the role of "Alex Crown" and from 1992–1995, he played the role of "Gen. Sloan Carpenter". During both of his stints on the show, his characters became a father-in-law to the same character, Cassie Callison.