Hull appeared in 74 films between 1917 and 1966, often playing supporting characters like the uncle of Tyrone Power's love interest Nancy Kelly in Jesse James (1939). He appeared as Charles Rittenhouse, a wealthy industrialist in Alfred Hitchcock's Lifeboat (1944). Other notable roles were as Abel Magwitch in the 1934 version of Great Expectations and in the last film of Director Tod Browning, Miracles for Sale (1939). He starred in Werewolf of London in 1935.

Hull had two brothers who were also actors. Shelley Hull was a popular leading man, who died in 1919 during the Spanish influenza epidemic. Shelley's wife, Josephine Hull, was an Oscar-winning character Actress. Hull's other brother, Howard, the eldest brother, was also an actor. He was married, until his death in 1937, to stage star Margaret Anglin. Henry Hull was quoted as saying he owed all his dramatic training to Anglin, with whom he had acted on stage.

Early in his career, Hull appeared frequently on Broadway; he created the role of Jeeter Lester in the long-running play Tobacco Road (1933), based on the novel by Erskine Caldwell.

Hull memorably portrayed a Doctor who Humphrey Bogart goes to for help in High Sierra, then also was cast in Colorado Territory, a western remake of the High Sierra story that starred Joel McCrea. He played a desert prospector who comes to Robert Ryan's rescue in Inferno in 1953.

In 1955, Hull appeared as a college professor forced to retire at sixty-five in an episode of CBS's sitcom, Meet Mr. McNutley, later renamed The Ray Milland Show. He guest starred on CBS's Appointment with Adventure, John Payne's NBC western series, The Restless Gun, and the syndicated crime drama, U.S. Marshal. In 1958, he was featured in Robert Culp's western series, Trackdown as "Moss" in episode "Three Legged Fox".

On December 13, 1960, Hull guest-starred on NBC's Laramie as an embittered rancher, Ben Parkison, who challenges Slim Sherman, played by series star John Smith, to a duel after Parkison's youngest son accidentally kills himself on Sherman ranch land. Ron Harper portrays Parkison's other son, Tom.

Hull also guest-starred in the series finale of Laramie, the episode "The Road to Helena" (May 21, 1963). Series character Slim Sherman, while in Cody, Wyoming, is hired by David Franklin, played by Hull, and his barmaid daughter, Ruth, portrayed by Maggie Pierce, to guide the pair to Helena, Montana, so that Franklin can return money that he had previously stolen. John M. Pickard also appears in this episode.

Hull's last film was The Chase (1966) with Marlon Brando and Robert Redford.

Hull was married to Juliet Van Wyck Fremont (1886–1971) from 1913 until her death in 1971. She was a granddaughter of Civil War general and Explorer John C. Frémont and Jessie Ann Benton, the daughter of Missouri Senator Thomas Hart Benton. The couple had three children, Henry Jr., Shelley (1919–2005; named after Henry's late brother) and Joan. When his wife died in 1971, Hull went to Britain to spend his last years with his daughter. He died in Cornwall at his daughter's residence on March 8, 1977.