Talman served for 30 months in the United States Army in the Pacific Theatre of World War II, beginning his Service as a private on February 4, 1942, at Camp Upton in Yaphank, Long Island, New York. He was ultimately commissioned a major during the war.

In the 1952 film Beware, My Lovely, in which Ida Lupino played a war widow terrorized by a MadMan in her home, a photograph of Talman was used for the picture of her late, heroic husband.

In 1953, Talman played a sadistic, psychopathic killer in a movie directed by Lupino, the film noir The Hitch-Hiker. The New York Times wrote, "William Talman, as the ruthless murderer, makes the most of one of the year's juiciest assignments."

His performance was also noted by Gail Patrick Jackson, executive Producer of the CBS-TV series Perry Mason (1957–66). Raymond Burr had initially auditioned for the role of Hamilton Burger, but Patrick encouraged him to lose 60 pounds and read for the lead role — which Burr successfully did. Patrick already had an actor in mind for the Los Angeles district attorney: "I'd seen a brilliant little movie, The Hitch-Hiker, and had to have Bill Talman as Burger — and he never disappointed us," Patrick said.

In 1958, a Journalist asked Talman how he felt about Burger losing to Mason week after week. Talman said, "Burger doesn't lose. How can a district attorney lose when he fails to convict an innocent person? Unlike a fist or gun fight, in court you can have a winner without having a loser. As a matter of fact, Burger in a good many instances has joined Mason in action against unethical attorneys, lying witnesses, or any one else obstructing justice. Like any real-life district attorney, justice is Burger's main interest."

Talman was married three times. His first marriage, to Actress Lynne Carter, lasted from just before Talman left for active Service in 1942 to September 1952 and produced one daughter, Lynda. His second wife was Actress Barbara Read. They married in 1953 and had one daughter, Barbie, and one son, william Whitney Talman III. The couple divorced on August 23, 1960. His third wife was Margaret Flanagan whom he married in 1963. Margaret had a son (Steve) and daughter (Debbie) from a previous marriage. william and Margaret had two children: a son, Timothy, and a daughter, Susan. Widow Margaret Talman outlived Talman by nearly 34 years, until her death (also from lung cancer related to smoking) in January 2002, at age 73.

Aside from his major supporting role in Perry Mason, Talman also guest-starred in various television series, including Wagon Train, Have Gun-Will Travel, Cimarron City, and Gunsmoke. After the 1966 cancellation of Perry Mason, Talman appeared on The Wild, Wild West and in a first-season episode of The Invaders, "Quantity: Unknown." This was his last on-screen acting role before his death.

Four weeks after filming the second public Service announcement, Talman died of lung cancer (that had metastasized to his liver, bones and brain) on August 30, 1968, at the age of 53, and was buried in the Court of Liberty, lot 833, at Forest Lawn Memorial Park (Hollywood Hills) in Los Angeles. His widow, Margaret "Peggy" Louise Talman, joined him there at the time of her death in January 2002, aged 73. After william Talman's death, she continued his antismoking efforts. Within a few years she had resumed smoking, and her cause of death was also lung cancer.