Johnson was born to parents Charles E. Johnson (who was born in Sweden) and Loretta, who was of Pennsylvania Dutch ancestry. His acting career began in earnest in 1936 in the Broadway revue New Faces of 1936.

In 1939 he landed a part in Rodgers and Hart's Too Many Girls in the role of a college boy (after being Gene Kelly's understudy in Pal Joey). RKO then signed him to a short-term contract to star in the film adaptation of the play which became Johnson's film debut. MGM picked up his contract from RKO soon after and cast him in several bit parts. In 1942, while en route to a preview screening for Keeper of the Flame, he was involved in a car crash that left him with a metal plate in his forehead. This left him exempt from service in World War II.

After this incident, MGM built up his image as the "all-American boy" by co-starring him in films with June Allyson and Esther Williams, among others. He also had his fair share of serious roles in films such as A Guy Named Joe and Thirty Seconds Over Tokyo.

When the studio system declined in the mid-1950's, Johnson's popularity did also due to his heavier-set appearance. He then left MGM for Columbia Pictures to co-star in The Caine Mutiny (1954) to much acclaim (His scar from the car crash is very visible in this film). Since 1960, his film career has been inconsistent.

Johnson has guest-starred on television shows such as Batman, Here's Lucy, and The Love Boat. Mr. Johnson also appeared in the 1970s ground breaking mini-series, "Rich Man, Poor Man,' with stars Peter Strauss and Nick Nolte.

In 1963, he underwent treatment for skin cancer.

In 1985, he enjoyed a sort-of comeback. He toured with the hit Broadway musical La Cage aux Folles and appeared in a supporting role in Woody Allen's The Purple Rose of Cairo.

For his contribution to the motion picture industry, Van Johnson has a star on the Hollywood Walk of Fame at 6600 Hollywood Blvd.

At the moment, he is enjoying a quiet life in retirement in New York. He is estranged from his daughter, Schuyler Johnson, from his marriage to the late Eve Lynn Abbott (who was formerly married to Keenan Wynn). She married Johnson under pressure from MGM Chief Louis B. Mayer (to put to rest rumours regarding Johnson's sexual orientation) on the day her divorce from Wynn was finalized, January 25, 1947. Their daughter was born a year later, and they divorced in 1968.

Eve Lynn Abbott Wynn Johnson died in 2004 at the age of 90. Her daughter confirmed to the The Globe (tabloid) that her father, Van Johnson, was a cold and disinterested father for most of her life, and that he does indeed have homosexual proclivities.