"Edward M. Kennedy - the husband, father, grandfather, brother and uncle we loved so deeply - died late Tuesday night at home in Hyannis Port," Massachusetts, the Kennedy family said in a statement.
"We thank everyone who gave him care and support over this last year, and everyone who stood with him for so many years in his tireless march for progress toward justice, fairness and opportunity for all.
"He loved this country and devoted his life to serving it."
The "liberal lion" of the Senate was the youngest of the Kennedy brothers.
President John F Kennedy was assassinated in 1963.
Senator Robert Kennedy was shot dead as he campaigned for the 1968 Democratic presidential nomination.
Joe Kennedy, a pilot, died in World War Two.