Born in Montréal, Québec, he moved to the United States at a young age. He studied at the University of California, Los Angeles then found work in the prop department at 20th Century Fox studios. He eventually went to work at RKO Pictures where he began training as a film editor. In 1940 he worked as an assistant to Robert Wise on the editing of Citizen Kane plus several other films until 1943 when he began directing a series of low-budget horror films produced by Val Lewton that today are regarded as some of RKO's best, including The Seventh Victim (1943), Robson's first directing credit, and Isle of the Dead (1945).

His success at RKO lead to work on major film projects and in 1949 he was nominated for the Directors Guild of America Award for Outstanding Directorial Achievement in Motion Pictures for his work on the film noir drama Champion. That same year, he directed the popular romance My Foolish Heart and Home of the Brave, one of the first films to deal with the issue of racism. He was nominated by the DGA again for the 1955 war drama The Bridges at Toko-Ri, starring William Holden and Grace Kelly.

In 1958, Mark Robson was nominated for an Academy Award for Directing for the major box office success Peyton Place and again the following year for directing Ingrid Bergman in the acclaimed film The Inn of the Sixth Happiness . For these films he also received his third and fourth Directors Guild of America nomination. Robson also produced a number of films which he also directed including Von Ryan's Express in 1965. He directed 1967's Valley of the Dolls, a film panned by the critics but a success at the box office. In 1974 he directed Earthquake, the film that introduced "Sensurround".

Mark Robson died of a heart attack in 1978 while in London, UK filming Avalanche Express. His remains were brought back to the U.S. for interment in Mount Sinai Memorial Park Cemetery in Los Angeles.

For his contribution to the motion picture industry, Mark Robson has a star on the Hollywood Walk of Fame at 1722 Vine Street.