In Europe, Arness reached cult status for his role as Zeb Macahan in the Western series How the West Was Won.

During that time, Arness worked as a courier for a jewelry wholesaler, loading and unloading railway boxcars at the Chicago, Burlington and Quincy Railroad freight yards in Minneapolis and logging in Pierce, Idaho.

[3] Arness entered Beloit College that fall, where he joined the campus choir and became a member of Beta Theta Pi fraternity.

[3] He was severely wounded in his right leg during the Battle of Anzio,[6] and medically evacuated from Italy to the US, where he was sent to the 91st General Hospital in Clinton, Iowa.

In his later years, he suffered from chronic leg pain that often became acute, and was sometimes initiated when he was mounted on horses during his performances on Gunsmoke.

[8][9] After his discharge from the service, Arness began his entertainment career as a radio announcer at Minneapolis station WLOL in 1945.

[8] Though identified as appearing in Westerns, Arness also acted in two science-fiction films, The Thing from Another World (in which he portrayed the titular character) and Them!.

An urban legend has it that John Wayne turned down the starring role of Matt Dillon in the classic television Western Gunsmoke, instead recommending James Arness for the part.

[14] Gunsmoke made Arness and his co-stars, Milburn Stone, Amanda Blake, Dennis Weaver, Ken Curtis, Burt Reynolds, and Buck Taylor world-famous, and ran for two decades, becoming the longest-running primetime drama series in American television history by the end of its run in 1975.

An exception was as a big-city police officer in a short-lived 1981–1982 series, McClain's Law, starring with Marshall Colt.

His role as mountain man Zeb Macahan in How the West Was Won made him a cult figure in many European countries, where it became even more popular than in the United States, as the series has been rebroadcast many times across Europe.

James Arness: An Autobiography was released in September 2001, with a foreword by Reynolds (who had been a cast member of Gunsmoke for several years in the 1960s).

[8] Despite his stoic character, according to Ben Bates, his Gunsmoke stunt double, Arness laughed "from his toes to the top of his head".

Arness was inducted into the Santa Clarita Walk of Western Stars in 2006, and gave a related TV interview.