Lil Hardin met Louis Armstrong in 1921 while they were both playing in King Oliver’s Creole Jazz Band. They married in 1924. It’s widely thought that her association with Louis made her one of the most prominent musicians of her time, but in truth, she was as much responsible for his fame as his rise to stardom was for hers. Hardin came to the marriage with a long history of professionalism in music, which continued throughout the marriage and afterwards. Prior to playing in King Oliver’s Creole Jazz Band, while working at a music store in Chicago, she became the most sought after pianist in Chicago. It was at that time she was invited to join Sugar Johnny Creole’s Orchestra. After that gig she joined Freddie Keppard’s Original Creole Orchestra,and then led her own band at Chicago’s Dreamland Café before joining King Oliver’s Creole Jazz Band.She was an accomplished pianist, arranger and composer.

It was Lil who persuaded Armstrong to leave King Oliver’s Creole Jazz Band and strike out on his own. While Louis was a very shy man, Lil was a deeply ambitious woman. She launched and managed his solo career, showing remarkable business savy. Additionally, Lil arranged for most of the important Hot Bands from New Orleans. On Armstrong’s Hot Five and Hot Seven recordings her playing was featured, she sang, and composed several of the group’s major songs.

Hardin was also the leader of several other recording groups, among them Lil’s Hot Shots and the New Orleans Wanderers. She appeared in the very successful Broadway shows "Hot Chocolates" and "Shuffle Along". As a swing vocalist Lil cut 26 sides for Decca records in the 1930s. She led one of the first all-female jazz bands in Harlem in 1931, and again in Chicago in 1934. Hardin moved back to Chicago and played solo piano in nightclubs in the 40s. She spent four very successful years in Europe in the 1950s. Lil continued her recording career until the early 1960s with musicians Johnny Dodds, Red Allen, Zutty Singleton , Frankie "Half-Pint" Jaxon, Lonnie Johnson, Buster Bailey , Natty Dominque, Lovie Austin, and Sidney Bechet.

Over the years Lil Hardin-Armstrong studied at Fisk College (Nashville, TN), completed formal music studies and earned a diploma from the Chicago Musical College, and a postgraduate degree from the New York College of Music. She also studied fashion and mounted a fashion show in New York in 1942.

Lil Hardin-Armstrong and Louis Armstrong were seperated in 1931 and divorced in 1938, but remained friends for life. And she continued to manage his career after his meteoric rise to stardom. She still lived in the house she and Louis bought together, and thought of herself as Mrs. Armstrong in many ways. A few weeks after Louis died in 1971, Lil participated in a televised memorial concert honoring him. She was introduced to the audience, took her seat at the piano, and began playing a joyful "St. Louis Blues". During her performance, she collapsed, suffering a massive heart attack.

The summer of 1971 held the death of not one, but two exceptional jazz artists: Louis Armstrong and Lil Hardin.