An operatic singer in the mold of Howard Keel, Presnell was performing throughout the country when composer Meredith Willson wrote the role of Johnny 'Leadville' Brown in "The Unsinkable Molly Brown" just for him. After earning kudos for his stage performance and his screen recreation, he seemed poised for a successful career. In 1965, he was cast alongside Liberace and the British rock group Herman's Hermits in "When the Boys Meet the Girls", a loose remake of the Gershwin musical "Girl Crazy" that was more showcase than movie; it died at the box office. But it was nothing compared with the misguided "Paint Your Wagon" (1969), which was a box office disaster. Presnell received good notices for his work, particularly for his rendition of "They Call the Wind Maria", but the film suffered from miscast leads (Jean Seberg, Lee Marvin and Clint Eastwood). The heyday of the Hollywood musical was nearly over and Presnell's feature career petered out.
Returning to the stage, Presnell appeared frequently in summer stock and on tour, playing roles like Frank Butler in numerous productions of Irving Berlin's "Annie, Get Your Gun". In 1979, he landed the role of Daddy Warbucks in the Broadway musical "Annie", and he later toured in the role, but lost the film version to Albert Finney. Presnell was tapped to reprise Warbucks in "Annie II: Miss Hannigan's Revenge" in 1990, but the show was plagued with problems and it never made it to New York. He also played Rhett Butler in a musical version of "Gone With the Wind" in London (Pernell Roberts had the dubious honor of appearing in the Los Angeles production.)
After more an absence of more than 25 years, Presnell was back in motion pictures. The Coen brothers cast him as an overbearing father-in-law whose stubborn streak costs him dearly in "Fargo" (1996). That same year, Presnell also co-starred opposite Bill Murray in "Larger Than Life", played the father of writer Robert E. Howard in "The Whole Wide World" (screened at the Sundance Film Festival) and portrayed the attorney general in James Foley's version of John Grisham's "The Chamber". Subsequent film roles have included 1997's "Face/Off", 1998's "Patch Adams" and "Saving Private Ryan" and 2000's "The Legend of Bagger Vance" and "Family Man".
Although he made some unsold pilots through the years, Presnell has rarely been seen on TV in dramatic roles. He played Matthew Crane on "Ryan's Hope" from 1984-85, during the waning days of the ABC soap opera. In 1995, he guest-starred on an episode of a dramatic primetime series for the first time with "John Grisham's The Client" (CBS). Also during the 1995-96 season, he played recurring role of Lois Lane's father in "Lois & Clark: The New Adventures of Superman" (ABC).