They lived in Joliet, Illinois, and, in the hope of starting a stage career, she began performing at talent shows in nearby Chicago. She adopted the stage name Nora Bayes: "Nora" as a shortened form of Eleonora, and "Bayes", according to one story because a local stage manager said that she would not have a good career with the name Goldberg. He suggested going through the Hebrew alphabet to find a name, and recited "Aleph, bays....", when she stopped him and suggested "Bayes".

By late 1900, Helen Cohan, the mother of George M. Cohan, saw her performing in vaudeville in Chicago. Bayes joined a touring company, performing in St Louis, Missouri and then California, before she decided to advance her career further and moved with her husband to New York City. She grew in popularity as a comic actress and singer, and in 1902 started performing Harry Von Tilzer's song, "Down Where the Wurzburger Flows", which she performed at the Orpheum Theatre in Brooklyn and which became her first big popular success.

Over the next few years, she performed in increasingly prestigious theatres in New York, toured the country, and between 1904 and 1907 made several tours in Europe. She first performed in London in December 1905, and was an immediate success.After returning to the United States, she performed regularly on B. F. Keith's theatre circuit. She and Gressing divorced in 1907, and soon afterwards she was approached by impresario Florenz Ziegfeld to star in a new theatre show, The Follies of 1907. The show, soon retitled The Ziegfeld Follies, was a huge success and established Bayes' status, making her one of the highest paid female performers in the world.

In 1908, she married fellow performer Jack Norworth, and the couple became media celebrities. They performed together, and were credited with co-writing the hit song "Shine On, Harvest Moon", included in the Ziegfeld Follies of 1908, along with several songs in the show. Bayes was the star performer, commanding a much higher salary than Norworth, and sometimes challenging the authority of theatre managers and promoters. She walked out of the Ziegfeld Follies of 1909 because of a disagreement with Ziegfeld over the billing of new rising star Sophie Tucker; Ziegfeld then took legal action against Bayes for breach of contract, which prevented her performing in other theatres for some months.

She and Norworth returned to the vaudeville circuit, in the show Miss Innocence, and commanded an even higher salary than before. "Critics noted that Bayes succeeded through her lush singing voice, her sensitivity to her audience’s tastes and her willingness to make fun of herself, including jokes about her Jewish background and her failed marriages." In 1910, they appeared together in Lew Fields' show, The Jolly Bachelors.

Bayes made her first recordings in 1910, for Victor Records, and had immediate success with "Has Anybody Here Seen Kelly", an Americanised version of a British song. She and Norworth recorded together, and continued to perform together until their last show, The Sun Dodgers, in 1912. However, their personal and professional relationships were unravelling, and they divorced in 1913. She was married to an actor and dancer, Harry Clarke, between 1913 and 1915.

She continued to find success on the Keith vaudeville circuit, billed as "The World's Greatest Singing Single Comedienne", before reuniting briefly with Norworth in the Broadway revue Odds and Ends of 1917. She then launched her own one-woman show, and starred in the musical Ladies First in 1918, in which she appeared with young piano accompanist George Gershwin.She also returned to recording, and had one of her greatest successes with the patriotic First World War song, "Over There", written by George M. Cohan. She signed a new contract with Columbia Records, and recorded over 60 songs with them over the next six years. Her most successful recordings for Columbia included "How Ya Gonna Keep 'em Down on the Farm (After They've Seen Paree)?" (1919) and "Make Believe" (1921).

She married for a fourth time in 1920, to actor and entertainer Arthur Gordon (sometimes billed as Gordoni). They adopted three (possibly four) children together, but divorced in 1922 after two years together. By this time, Bayes' success was diminishing; she made no recordings after the end of her Columbia contract in 1923, bookings decreased, and she was performing in smaller venues. She refused to take part in the expanding film industry, claiming that she would make too much money and that "the mental anguish I would suffer would make me unfit to enjoy life. No, siree. No movie work for me!"

She made several trips to Europe in the early 1920s, travelling with her adopted children. Bayes was described as "easily the most popular female entertainer in vaudeville for much of the first quarter of the 20th century". One researcher commented:

Bayes refused to obey the social mores that ruled expectations of how women should behave. Her personal life caught the attention of the press: she provided endless headlines for her broken theatre contracts and her five divorces. Her marriages were reported across the globe. On news of her fifth marriage, one Australian newspaper reported her advice to wives: “as soon as one becomes bored, one should secure divorce.” The press hardly knew which was more shocking, her divorces or the fact she had walked out of her contract with Florenz Ziegfeld.