Lewis, who teamed up with Dean Martin in the 1950s, and later starred in "The Nutty Professor" and "The Bellboy", died of natural causes at his Las Vegas home on Sunday, his publicist, Candi Cazau, said in a statement.
He injured his back during a comedic skit in 1965.
He also suffered from a heart attack in 2006 and a long bout with pulmonary fibrosis, a chronic lung disease.
Lewis was more than an actor, he was also a humanitarian.
Lewis was rushed to a hospital in 2011 just moments before he was scheduled to perform for a sold-out audience in Sydney, Australia, media reports stated.
Their stint together began at the 500 Club in Atlantic City, when a performer canceled on Lewis, leading the comedian to tell the club to book Martin."I fell in love with him the day we met".
According to the Associated Press, he was touring the country to raise money for the Australian foundation, and had performed in Brisbane earlier in the week.
Comedian Jerry Lewis, known for his work in film as well as hosting an annual telethon for the Muscular Dystrophy Association, has passed away at 91.
In 2010, pledges and donations to the MDA Telethon brought in $58.9 million, the organization's website states.
Jerry Lewis in 2015.
Lewis was born in New Jersey and originally came into the spotlight as part of a double act with singer Dean Martin. He raised almost $2.5 billion by the late 2000s through his telethons - he was also nominated for a Nobel Peace Prize in 1977 for his efforts in raising awareness and money for the disease.
Lewis had five sons and adopted another child with his first wife Patti Palmer.