She was born Sophia Kalish to a Jewish family in Czarist Russia; her family emigrated to the United States when she was an infant and settled in Hartford, Connecticut. In 1903, at the age of 19, she was briefly married to Louis Tuck; from which she decided to change her name to "Tucker." (She would marry twice more in her life, but neither marriage lasted more than five years.)

Tucker played piano and sang burlesque and vaudeville tunes, at first in blackface. She later said that this was at the insistence of theater managers, who said she was "too fat and ugly" to be accepted by the audience in any other context. She even sang songs that acknowledged her heft, like "Nobody Loves a Fat Girl, But Oh How a Fat Girl Can Love."

She made a name for herself in a style that was known at the time as a "Coon Shouter", performing African American influenced songs. Not content with performing in the simple minstrel traditions, Tucker hired some of the best African American singers of the time to give her lessons and hired African American composers to write songs for her act.

At a 1908 appearance the luggage containing Tucker's makeup kit was stolen shortly before the show, and she hastily went on stage without her customary blackface. To the theater manager's surprise, Tucker was a bigger hit without her makeup than with it, and she never wore blackface again. She did, however, continue to draw much of her material from African American writers and culture, singing in a ragtime- and blues-influenced style, becoming known for a time as "The Ragtime Mary Garden," a reference to a famous operatic soprano of the era.

Tucker made her first appearance in the Ziegfeld Follies in 1909, but didn't last long there because Florenz Ziegfeld's other female stars soon refused to share the spotlight with the popular Tucker.

She made the first of her several recordings of "Some of These Days" in 1911 for Edison Records. The tune, written by Shelton Brooks, was a hit and became Tucker's theme song, and later was the title of her 1945 autobiography.

In 1921 Tucker hired pianist and songwriter Ted Shapiro as her accompanist and musical director, a position he would keep throughout her career. Besides writing a number of songs for Tucker, Shapiro became part of her stage act, playing piano on stage while she sang, and exchanging banter and wisecracks with her in between numbers.

Tucker remained a popular singer through the 1920s, and hired stars such as Mamie Smith and Ethel Waters to give her lessons. She also made the first of her many movie appearances in the 1929 sound picture Honky Tonk.

In the 1930s Tucker brought elements of nostalgia for the early years of 20th century into her show. She was billed as The Last of the Red Hot Mamas as her hearty sexual appetite was a frequent subject of her songs, unusual for female performers of the era. She made numerous popular film appearances, including Broadway Melody of 1938. In that film Tucker sings a song during the big finale; even though she is playing a character and not herself, several neon lights displaying her real name light up in the background of the stage in tribute.

In the 1950s and early 1960s she made television appearances on The Ed Sullivan Show, What's My Line, and The Tonight Show.

She continued performing in the U.S. and the United Kingdom until shortly before dying of lung cancer in 1966 at the age of 82.