Frawley did two years of office work at Union Pacific Railroad in Omaha, Nebraska; he later moved to Chicago and found a job as a court reporter. Shortly thereafter, against his mother's wishes, Frawley landed a singing part in the musical comedy The Flirting Princess. After the news reached his mother, she was greatly dismayed. To appease her, Bill moved to St. Louis, Missouri to work for another railroad.
Unhappy in his railroad job, Frawley longed for the stage. He finally decided he couldn't resist and formed a vaudeville act with his younger brother, Paul. Six months later, Frawley's mother ordered Paul back to Iowa. It was during this period that Bill wrote a script called Fun in a Vaudeville Agency. He earned over five hundred dollars for his efforts; after this, he decided to move West, ending up in Denver, Colorado. He was hired as a singer at a café, and after building up a strong reputation, teamed with pianist Franz Rath. The two men headed to San Francisco with their act, "A Man, a Piano, and a Nut." During his vaudeville career, Frawley introduced and helped popularize the songs "My Mammy" , "My Melancholy Baby", and "Carolina in the Morning". Years later in 1958, he recorded many of his old stage songs on the LP William Frawley Sings the Old Ones. In 1965, he appeared on the CBS-TV show "I've Got A Secret", where he sang "My Melancholy Baby" to the panel after revealing his secret (that he first introduced this famous song).
In 1914, Frawley married fellow vaudevillian Edna Louise Broedt. They developed an act, "Frawley and Louise", which they performed all across the country. Their act was described as "light comedy, with singing, dancing, and patter." The couple separated in 1921 (later divorcing in 1927). The couple had no children. Soon, Frawley moved on to Broadway. His first show was the musical comedy Merry, Merry in 1925. Frawley made his first dramatic role in 1932, playing press agent Owen O'Malley in the original production of Ben Hecht and Charles MacArthur's Twentieth Century. He continued to act on and off Broadway until 1933.
Back in 1916, Frawley had appeared in two short subject silent films. He made subsequent appearances in three other short films, but it wasn’t until 1933 that he decided to pursue an ongoing career in the movies. He soon moved to Los Angeles and signed a seven year contract with Paramount Pictures. Finding much work as a character actor, he had roles in many different genres of films — comedies, dramas, musicals, westerns, and romances. A notable appearance was made in the 1947 holiday favorite Miracle on 34th Street as Judge Harper's political adviser (who warns his client in great detail the dire political consequences if he rules that there is no Santa Claus). Another memorable film role was his police detective in Charlie Chaplin's Monsieur Verdoux (1947).
Actor Gale Gordon, a friend of Lucille Ball's, was the first choice to play the character. Gordon was unavailable, however, due to a prior commitment. One evening, Frawley phoned Lucille Ball, asking her what his chances were. Ball was surprised to hear from him — a man she only barely knew from the 1940s. Both Ball and Arnaz agreed that it would be great to have Frawley, a motion picture veteran, appear as Fred Mertz. Less enthusiastic were CBS executives, who warned Desi of Bill's heavy drinking and instability. Arnaz immediately leveled with Frawley about the network's concerns, telling him that if he was late to work, showed up drunk, or was unable to perform except because of legitimate illness more than once, he'd be written out of the show. To the contrary, Frawley never showed up drunk to work, and, in fact, mastered his lines after only one reading. Arnaz became one of his closest friends.
I Love Lucy, which debuted October 15, 1951 on CBS, was a huge success. The show ran for six years as half-hour episodes, later switching to hour-long specials from 1957 to 1960 titled The Lucille Ball-Desi Arnaz Show (later retitled The Lucy-Desi Comedy Hour).
Vivian Vance played Ethel Mertz, Frawley’s on-screen wife. Although the two actors shared a great comedic and musical chemistry on-screen, they greatly disliked each other in real life. Most attribute their mutual hatred to Vance's vocal resentment of having to play wife to a man 22 years her senior. Frawley reportedly overheard Vance complaining; he took offense and never forgave her. "She's one of the finest girls to come out of Kansas," he once observed, "But I often wish she'd go back there."
A rabid New York Yankees baseball fan, Frawley had it written into his I Love Lucy contract that he did not have to work during the World Series if the Yankees were playing.
For his work on the show, Frawley was Emmy-nominated five times (for 1953, 1954, 1955, 1956 and 1957) for "Outstanding Supporting Actor" in a comedy series.
In 1960, Ball and Arnaz gave Frawley and Vance the opportunity to star in their own "Fred and Ethel" spin-off series for Desilu Studios. Despite his animosity towards her, Frawley saw a lucrative opportunity and accepted. Vance, however, declined the offer and the series was nixed.
Frawley reportedly never felt comfortable with the out-of-sequence filming method used on My Three Sons after doing I Love Lucy in sequence for years. Each season's episodes were arranged so that star Fred MacMurray could shoot all of his scenes during two separate intensive blocks of filming for a total of 65 working days on the set; Frawley and the other actors worked around the absent MacMurray for the remainder of the year's production schedule.
Poor health forced Frawley's retirement from the show after five years. He was dropped from My Three Sons after the studio could no longer obtain insurance on him. He was replaced by actor William Demarest.
On March 3, 1966, Frawley collapsed of a heart attack while walking down Hollywood Boulevard after seeing a movie. He was dragged to the nearby Knickerbocker Hotel, where he had previously lived for many years, by his male nurse — a constant companion since his prostate cancer operation more than a year before. He was then rushed to the nearby Hollywood Receiving Hospital, where he was pronounced dead.
Shortly following his death, Desi Arnaz paid for a full-page ad in the Hollywood Reporter. It had a picture of Frawley, surrounded in black, the dates of his life and death, and the caption, "Buenas Noches, Amigo!" ("Good Night, Friend").
Lucille Ball issued the statement: "I've lost one of my dearest friends and show business has lost one of the greatest character actors of all time. Those of us who knew him and loved him will miss him."
He is buried in the San Fernando Mission Cemetery in Mission Hills, Los Angeles, California.
For his achievements in the field of motion pictures, Frawley was awarded a star on the Hollywood Walk of Fame at 6322 Hollywood Blvd.
Frawley is memorialized in the Lucille Ball-Desi Arnaz Center in Jamestown, New York, which also contains his "Froggie" costume from an episode of I Love Lucy. (See also SaveLucyDesiCenter.org)