Burke was nominated for the Academy Award for Best Supporting Actress for her performance as Emily Kilbourne in Merrily We Live (1938). She is also remembered for her appearances in the Topper film series. Her unmistakably high-pitched, quivering and aristocratic voice, made her a frequent choice to play dimwitted or spoiled society types.

She was married to Broadway producer and impresario Florenz Ziegfeld Jr. from 1914 until his death in 1932.

Burke went on to play leads on Broadway in Mrs. Dot,^[2] Suzanne,^[3] The Runaway, The "Mind-the-Paint" Girl, and The Land of Promise from 1910 to 1913, along with a supporting role in the revival of Sir Arthur Wing Pinero's The Amazons. There she met producer Florenz Ziegfeld, marrying him in 1914. Two years later they had a daughter, author Patricia Ziegfeld Stephenson (1916–2008).^[4]

Burke was signed for the movies and made her cinematic debut in the title role of Peggy (1915). Her success was phenomenal, and she was soon earning what was reputedly the highest salary of any film actress up to that time.^[5] She followed her first feature with the 15-part serial Gloria's Romance (1916), another popular and critically acclaimed vehicle. By 1917, she was a favorite with silent-movie fans, rivaling Mary Pickford, Lillian Gish, Clara Kimball Young and Irene Castle. She starred primarily in provocative society dramas and comedies, similar in theme to The "Mind-the-Paint" Girl, her most successful American play. Her girlish charm rivaled her acting ability, and as she dressed to the hilt in fashionable gowns, furs and jewelry, her clothes sense also won her the devotion of female audiences. Among the films in which she appeared during this period were Arms and the Girl (1917), The Mysterious Miss Terry, Let's Get a Divorce (1918), Good Gracious, Annabelle (1919), Away Goes Prudence (1920) and The Frisky Mrs. Johnson (1920). As a nod to himself for his wife appearing for Zukor and Lasky, Ziegfeld insisted on promotions for each of the films to carry the tag 'By Special Arrangement with Florenz Ziegfeld'.

Burke's beauty and taste made her a major trendsetter throughout the 1910s and 20s. As early as 1909, following her Broadway performance in My Wife (1909), department stores began carrying the "Billie Burke Dress" with a signature flat collar and lace trim."^[6] During this time, much of Burke's on- and off-screen wardrobe was provided by the leading European couturier Lucile (in private life, Lady Duff Gordon), whose New York branch was the fashion Mecca of socialites and entertainment celebrities.^[7] Burke reflected on her reputation as "a new kind of actress, carefree, and red-headed, and I had beautiful clothes."^[8]

Despite her success in film, Burke eventually returned to the stage, appearing in Caesar's Wife (1919), The Intimate Strangers (1921), The Marquise (1927) and The Happy Husband (1928). When the family's investments were wiped out in the Wall Street Crash the following year, she resumed screen acting to aid her husband.

Burke made her Hollywood comeback in 1932, when she starred as Margaret Fairfield in A Bill of Divorcement, which was directed by George Cukor. She played Katharine Hepburn's mother in the film, which was Hepburn's debut. Despite the death of her husband Florenz Ziegfeld during the film's production, she resumed acting shortly after his funeral.

In 1933, Burke was cast as Millicent Jordan, a scatterbrained high-society woman hosting a dinner party in the comedy Dinner at Eight, directed by George Cukor, co-starring with Lionel Barrymore, Marie Dressler, John Barrymore, Jean Harlow and Wallace Beery. The movie was a great success and revitalized her career. She subsequently starred in many comedies and musicals, typecast as a ditzy, feather-brained upper-class matron, with her high-pitched voice.

In 1936, MGM filmed a biopic of Florenz Ziegfeld (The Great Ziegfeld), a film that won Academy Awards for Best Picture and Best Actress (Luise Rainer as Ziegfeld's common-law wife, Anna Held). William Powell played Ziegfeld and Myrna Loy played Burke; this infuriated Burke, who was under contract to the studio and believed she could have played herself, however, MGM considered her too old to cast in the part of her younger self.

Burke appeared in Topper (1937) in which she played the twittering and puritan Clara Topper, who is married to a man haunted by socialite ghosts played by Cary Grant and Constance Bennett. She returned to the role in the film's sequels. Her next performance as Emily Kilbourne in Merrily We Live (1938) resulted in her only Oscar nomination. In 1938, she was chosen to play Glinda the Good Witch of the North in the musical The Wizard of Oz (1939), directed by Victor Fleming, starring Judy Garland. She had previously worked with Garland in the film Everybody Sing, in which she played Judy's histrionically hysterical actress-mother. Director George Cukor offered her the role of Aunt Pittypat in Gone With the Wind (1939), but she declined and it was played by Laura Hope Crews, a character that Cukor wanted to be played in a "Billie Burke-ish manner" with "the same zany feeling".^[9] Another successful film series followed with Father of the Bride (1950) and Father's Little Dividend (1951), both directed by Vincente Minnelli and starring Spencer Tracy, Joan Bennett, and Elizabeth Taylor. Burke also portrayed Mrs. Ernest (Daisy) Stanley in the 1942 film The Man Who Came to Dinner.

Burke wrote two autobiographies, both with Cameron Shipp, With a Feather on My Nose (Appleton 1949) and With Powder on My Nose (Coward McCann, 1959).