In 1916 Brice returned to the Ziegfeld Follies with her popular skit "The Blushing Bride." She remained with Ziegfeld until 1924, in all appearing in seven editions of the Follies and four revues.

Brice was considered to be one of the greatest comediennes on Broadway. Although she was an attractive, graceful woman offstage, she elicited the audience's sympathy and laughter by bringing out the imperfections of her characters. She could be ugly, lack grace, and be mischievous— all for a laugh. She could bring out pathos and at the same time mock sentimentality. In her vaudeville number "You Made Me Love You" the first half was a heart rending song, followed by Brice laughing at her own sentiment by kicking her heels, winking her eyes, swinging on the curtain, and then lifting her skirt to show off her knock knees Not only did she make fun of herself but she parodied standard theatrical styles and actors of the period, such as the Barrymores. Brice also appeared several times with W. C. Fields in a popular family sketch.

In 1921 Brice introduced "My Man" to American audiences. She stood on an empty stage against a lamppost and sang the painful song about a woman whose total devotion to her "man" had brought nothing but unhappiness. Perhaps the pathos she brought to that character was from her personal experience—her husband, Nickie Arnstein, had just been jailed for embezzlement and she had to stand by him. This was one of her few totally straight performances, and it is one for which she will be remembered.

In 1924 Brice, displeased with the material Ziegfeld was giving her, returned to vaudeville for a time. She played the lead role in the film "My Man" and then appeared in Billy Rose's (her third husband) Sweet and Low (1930) in which she introduced "Babykins," a three year old in a high chair. This character was the starting point for another Brice trademark, "Baby Snooks."

In the Shubert's 1936 Follies she did a spoof of "My Man" in which she said that she had been singing about "that bum" for more than 15 years. This satire on the sentiment in the song was much more her style than the straight emotionality of the earlier delivery. In the same show she did a parody of Shirley Temple in an act with Bob Hope in which she played a child star who couldn't remember her lines.

Due to ill health Brice left Broadway for Los Angeles, where she made a few film appearance, including MGM's Ziegfeld Follies (1946) (she was the only Ziegfeld star who appeared in this film). She also immortalized "Baby Snooks" during her ten year radio series.

Despite her work in film Brice was a daughter of the stage. She knew exactly how to reach an audience and she gave her whole self with no reserves. During each performance she would get bigger and bigger until she seemed to envelop the audience with her whole being.

In 1938 Rose of Washington Square, a film suggesting the life of Brice, was made and Brice sued the producer. Yet it was through another film and Broadway show, Funny Girl, in which Brice was played by Barbra Streisand, that Brice's unique contributions to the theater became known to later generations. A fantasized version of her life focussing on her Ziegfeld days and her marriage to Nickie Arnstein, the play brings back to life her favorite characters and songs. Through this play her life has become inextricably linked with that of her characters, Sadie and "Second Hand Rose"—the poor but spunky Jewish city girls.

Aside from her theater career, Brice was a dress designer, painter, and interior decorator. She had two children, William and Frances. She died May 19, 1951, of cerebral hemorrhage, at the age of 59.