Talbot had several brief marriages, to Elaine Melchoir (1930-32), Abigail Adams (1942) and Keven McClure (1946) and a number of romantic entanglements. In 1948, he married for the fifth time, to Actress and singer Paula (née Margaret) Epple. She was 20, and he was a 46-year-old actor with a drinking Problem.
He briefly established his own theater company in Memphis, Tennessee. He went to Hollywood in 1931, when the film industry began producing movies with sound and needed "actors who could talk". His screen test at Warner Bros. was watched and appreciated by studio production chief Darryl F. Zanuck and, even more so, by Director william Wellman who immediately wanted to cast Talbot. Talbot became a contract player at Warners along with the likes of Future stars Bette Davis and Humphrey Bogart.
Most notable among Talbot's film work were his appearances in Three on a Match and 20,000 Years in Sing Sing (both 1932). He played a star running back in College Coach (1933) with Pat O'Brien and Dick Powell, romanced opera singer Grace Moore in One Night of Love in 1934, and pursued Mae West in Go West, Young Man (1936). He was a gangster in Ladies They Talk About and Heat Lightning and a Doctor kicking a drinking habit in Mandalay. He co-starred with Pat O'Brien in Oil for the Lamps of China (1935).
Early in his career at Warners, Talbot took part in one of Hollywood's most extravagant and ambitious publicity junkets, barnstorming across the country with Bette Davis, Cowboy star Tom Mix, Comedian Joe E. Brown, boxer Jack Dempsey and a host of WB actors and chorus girls on "the 42nd Street Special," a train covered in silver and gold leaf and electric Lights. With stops in dozens of cities, they were promoting the new Busby Berkeley musical and ended up in Washington, D.C. at Franklin Delano Roosevelt's first inauguration in March 1933 in a show of the studio's support for the new President. The press dubbed Talbot the train's "Romeo" and described him as "handsome as hell" and "likable as a collie."
Although Talbot once starred in a film called Trapped by Television (1936), the invention of TV actually revived his acting career, as his movie roles faded. Talbot was a frequent presence on American television from the 1950s well into the 1970s with occasional appearances in the 1980s. From 1955–66, he appeared in some seventy episodes of The Adventures of Ozzie and Harriet, as neighbor Joe Randolph. He also had a recurring role (1955–58) as Robert Cummings's character's buddy from the Air Force, Paul Fonda, in numerous episodes of The Bob Cummings Show.
Having started his career in the theater and later co-starred on Broadway in 1940-1941 in Separate Rooms, Talbot returned to the stage in the 1960s and 1970s, starring in national road company versions of Thornton Wilder's The Matchmaker, Gore Vidal's The Best Man, Neil Simon's The Odd Couple and Barefoot in the Park, Arthur Sumner Long's play Never Too Late, and appearing as Captain Brackett in a 1967 revival of South Pacific (at Lincoln Center). He also starred in Preston Jones' "The Last Meeting of the Knights of the White Magnolia" at the Alley Theater in Houston and the Chicago area Lincolnshire Theater. He rode the wave of the dinner theater phenomenon in the 1970s, acting in light comedies onstage in various Midwestern towns where former television actors were major attractions.
From 1950–55, he was cast five times in different roles on the western, The Lone Ranger. In 1955, he appeared as Baylor in six episodes of the series, Commando Cody: Sky Marshal of the Universe. From 1953–57, he was cast as different characters in four episodes of the anthology series, Lux Video Theatre. In 1967, he played Colonel Blake three times on The Beverly Hillbillies, and also appeared three times (between 1965–71) on Green Acres. On one episode of Green Acres Talbot played himself, as a senator, in a spoof on actors who became politicians. In 1959, Talbot played Sheriff Clyde Chadwick in the episode "The Sanctuary" on Colt .45.
Under Epple's influence, Talbot quit drinking. The couple had four children and they occasionally worked together on the stage. They remained married for more than forty years until her death in 1989.
Talbot died in 1996 at his home in San Francisco, California, aged 94, from congestive heart failure.