The pair’s eight-month journey around Latin America was immortalised in the 2004 film The Motorcycle Diaries.
The journey, begun in 1951, exposed the two medical students to deep poverty and social injustice and awoke Guevara’s revolutionary convictions.
After helping Fidel Castro overthrow Cuban dictator Fulgencio Batista in 1959, Guevara invited Granado to Cuba.
Cuban state media said he died of natural causes in Havana.
After arriving in Cuba in 1961, Granado taught biochemistry at Havana University.
His body is to be cremated and according to his wishes, the ashes are to be spread in Cuba, Argentina and Venezuela, Cuban television said.
Granado was born in Cordoba, Argentina, on 8 August 1922 and met Guevara as a child.
The film of their travels around Latin America on the motorcycle they called La Poderosa – The Powerful – was based on diaries both men kept.
Che Guevara was killed in Bolivia in 1967 as he tried to lead a revolution there.
In the 2004 film, Granado was played by Argentine actor Rodrigo De la Serna. Gael Garcia Bernal played Che.