In 1914, 16-year-old Samuel and another youth named Wallace Ford decided to head south to the United States to seek their fortune, riding a freight train illicitly. During the trip, Ford was killed beneath the wheels of a train. Later, Samuel adopted as his stage name the name of his dead traveling companion.

Following military Service as a trooper at Fort Riley, Kansas, with the United States Army Cavalry during World War I, he became a vaudeville stage actor in an American stock company. In 1919, he performed in an adaptation of Booth Tarkington's Seventeen, which played to full houses in Chicago for several months, before transferring to a successful run on Broadway in New York City. Ford became a successful Broadway performer through the Roaring Twenties, appearing in multiple productions, including the lead role in the Broadway smash hit Abie's Irish Rose.

Ford met his Future wife Martha Haworth in 1922 while they were performing together on Broadway in Abie's Irish Rose, she being a chorus girl at the time. They had one child, a daughter named Patricia (1927-2005).

In motion pictures, he appeared with Clark Gable and Joan Crawford in Possessed in 1931, and the next year he was given the lead in Metro-Goldwyn-Mayer's Freaks. Ford went on to have an extensive career over 30 years, appearing in more than 150 films, with lead roles in the 1930s and '40s in Hollywood B movies such as The Rogues' Tavern (1936), Murder by Invitation (1941), and Roar of the Press (1941), and supporting roles in larger feature films such as The Lost Patrol (1934), Shadow of a Doubt (1942), Spellbound (1945), and Dead Reckoning (1947).

In 1937, he returned to the Broadway stage to play the role of George in the original production of Of Mice and Men.

In 1945, Ford appeared in the film Blood on the Sun alongside Jimmy Cagney, whose physique and acting style resembled his own. In the late 1940s and early 1950s, he transitioned into a character actor, appearing as a regular performer in the newly fashionable Western genre, and in multiple John Ford productions as one of his preferred support players.

In the latter stage of his career, during the 1950s and early 1960s, Ford performed increasingly on television. His final appearance on the "small screen" was on The Andy Griffith Show in 1964, playing "Roger Hanover", Aunt Bee's old flame. The next year he appeared in his last film, A Patch of Blue, for which he received a Golden Laurel nomination. Ford's performance as "Ole Pa" in A Patch of Blue also proved to be the final role of his extensive acting career.

After the death of his wife in February 1966, Ford moved into the Motion Picture & Television Country House and Hospital at Woodland Hills, California, and died in the hospital there of heart failure four months later. His body was buried in an unmarked grave at Culver City's Holy Cross Cemetery.