The former Attorney General's family has announced that she died from complications relating to Parkinson’s disease, which she was diagnosed with in November 1995, while she was still in office.
Her granddaughter Gabrielle D’Alemberte said Ms Reno spent her final days at home in Miami surrounded by family and friends.
During her eight years in office as part of the Clinton administration, she was at the heart of several political storms including the custody battle of Elian Gonzalez, in 2000.
Mr González, a young Cuban refugee, was handed over to his father in Cuba after an international custody battle with his US relatives.
Ms Reno, who was 78 when she died, was the daughter of two journalists.
She was born July 21, 1938, and was the eldest of four siblings.
After graduating from Cornell University with a degree in chemistry, the politician became one of 16 women in Harvard Law School’s Class of 1963.
Other controversies she was connected to during her tenure included a deadly federal raid on the compound of a religious cult in Waco, Texas, in 1993.
During the raid the cult’s leader David Koresh and some 80 followers died.
Ms Reno was also linked to other scandals that marked the Clinton administration, including Monica Lewinsky, alleged Chinese nuclear spying and questionable campaign financing in the 1996 Clinton-Gore re-election.
Ms Reno's goddaughter, Gabrielle D’Alemberte, said that Janet Reno spent her final days at home in Miami surrounded by family and friends.