Little Richard's hit Good Golly Miss Molly made the charts in 1958. Other well-known songs include Tutti Frutti and Long Tall Sally.
The Beatles, Elton John and Elvis Presley all cited him an influence. The singer was inducted into the Rock and Roll Hall of Fame in 1986.
He died of bone cancer in Tullahoma, Tennessee his family said.
Little Richard was born as Richard Wayne Penniman in 1932.
He had his biggest hits in the 1950s and was known for his exuberant performances, shrieks, raspy voice and flamboyant outfits. He sold more than 30 million records worldwide.
Paying tribute after news of his death emerged, former Beatles drummer Sir Ringo Starr tweeted: "God bless Little Richard, one of my all-time musical heroes."
Chic co-founder Nile Rodgers said it was "the loss of a true giant", while Brian Wilson of the Beach Boys said his music would "last forever".
Richard's bass guitarist, Charles Glenn, told celebrity news website TMZ the singer had been ill for two months. He said Richard died at his home, with his brother, sister and son beside him.
Little Richard was one of 12 children, and said he had started singing because he wanted to stand out from his siblings.
"I was the biggest head of all, and I still have the biggest head," he told the BBC in 2008.
"I did what I did, because I wanted attention. When I started banging on the piano and screaming and singing, I got attention."
His music was embraced by both black and white fans at a time when parts of the US were still segregated, and concerts had a rope up the centre of the auditorium to divide people by colour.