Johnson was the embodiment of the "boy next door", playing "the red-haired, freckle-faced soldier, sailor or bomber pilot who used to live down the street" in MGM movies during the war years. At the time of his death in December 2008, he was one of the last surviving matinee idols of Hollywood's "golden age."

Johnson was born Charles Van Dell Johnson in Newport, Rhode Island; the only child of Loretta (née Snyder), a homemaker and Charles E. Johnson, a plumber and later real-estate salesman. His father was an immigrant from Sweden and his mother had German-American Pennsylvania Dutch ethnicity. His mother, an alcoholic, left the family when her son was a child; Johnson's relationship with his father was chilly.

Johnson performed at social clubs in Newport while in high school. He moved to New York City after graduating from high school in 1935 and joined an off-Broadway revue, Entre Nous (1935).

After touring New England in a theatre troupe as a substitute dancer, his acting career began in earnest in the Broadway revue New Faces of 1936. Johnson returned to the chorus after that, and worked in summer resorts near New York City. In 1939, director and playwright George Abbott cast him in Rodgers and Hart's Too Many Girls in the role of a college boy and as understudy for all three male leads. After an uncredited role in the film adaptation of Too Many Girls (which costarred Lucille Ball and Desi Arnaz), Abbott hired him as a chorus boy and Gene Kelly's understudy in Pal Joey.

Johnson was about to move back to New York when Lucille Ball took him to Chasen's Restaurant, where she introduced him to an MGM casting director Billy Grady, who was sitting at the next table.

This led to screen tests by Hollywood studios. His test at Columbia Pictures was unsuccessful, but Warner Brothers put him on contract at $300 a week. His all-American good looks and easy demeanor were ill-suited to the gritty movies Warner made at the time, and the studio dropped him at the expiration of his six-month contract. Shortly before leaving Warner, he was cast as a cub reporter opposite Faye Emerson in the 1942 film Murder in the Big House. His eyebrows and hair were dyed black for the role.

Fortuitously for Johnson, Lew Ayres, who played the title role in the popular Dr. Kildare movie series, was leaving to join the US Army as a medical corpsman. Ayres had played a young doctor who assisted the crusty Dr. Gillespie, played by Lionel Barrymore. Johnson was assigned to the new role of Dr. Randall Adams in Dr. Gillespie's New Assistant and Dr. Gillespie's Criminal Case, and he appeared as a bit player in two other MGM features. At the same time he was given the classes in acting, speech, diction and other disciplines that were provided to all contract actors at MGM at the time.

He subsequently appeared in Pilot No. 5 (1943) and in William Saroyan’s The Human Comedy, which was produced in 1943, and in the title role in Two Girls and a Sailor.

His big break was in A Guy Named Joe, with Spencer Tracy and Irene Dunne, in which he played a young pilot who acquires a deceased pilot as his guardian angel. Midway through the movie's production in 1943, he was involved in a car crash that left him with a metal plate in his forehead. Dunne and Tracy insisted that Johnson not be removed from the cast despite his long absence. The injury exempted Johnson from service in World War II.

With many actors now serving in the armed forces, the accident proved to be a major career break for Johnson. MGM built up his image as the all-American boy in war dramas and musicals, with his most notable starring role as Ted Lawson in Thirty Seconds Over Tokyo, which told the story of the Doolittle raid on Tokyo in April 1942.