Lewis, who starred in slapstick comedy films during the 1950s, died at his home in Las Vegas.
"Famed comedian, actor and legendary entertainer Jerry Lewis passed away peacefully today of natural causes at 91 at his home in Las Vegas with his family by his side," his family said in a statement.
The actor was renowned for his ten-year partnership with Dean Martin, entertaining audiences in nightclubs, on TV and the big screen.
After their split in 1956, he starred in and directed a number of hit films.
In 1960, Lewis made his movie directorial debut with The Bellboy and starred in the storybook parody Cinderfella.
Three years later he directed and starred in his most popular movie, The Nutty Professor, which was reinvented by Eddie Murphy in 1996.
He retired from making films in 1995 but returned as the star of 2016 drama Max Rose when he was 87.
Lewis starred in more than 45 films in a career spanning five decades.
He was very popular in France, and was inducted into the Legion of Honour in 1984, the country's highest award.
"The French are very visually oriented even though they are cerebral. They enjoy what they see and laugh. Then, later, they ask why," he once said.
He once summed up his career by saying: "I've had great success being a total idiot" and said the key was maintaining a certain childlike quality.
Later generations knew him primarily as the conductor of weekend telethons to raise funds for victims of muscular dystrophy.
His spokeswoman, Candi Cazau, told CNN on Sunday his annual telethon raised more than $2bn for the fight against the disease.
Cazau said the actor was planning to make stage appearances over the next few months in New York, and in Las Vegas next year.
Jerry Lewis was born Joseph Levitch on 16 March, 1926, in Newark, New Jersey, and started out on New York's Borscht Belt comedy circuit as a singer at the age of five.