Castro's departure stirred public reaction on Tuesday with the US president issuing a statement during his stay in Rwanda, as part of his Africa tour.
Speaking from the capital Kigali, George Bush, said the ailing leader's decision to step down should begin a "democratic transition" there, eventually culminating with free and fair elections.
His stepping down was likely to be welcomed by the US, although most Cubans have known no other leader.
Castro's statement comes five days before the country's national assembly session in which he was up for re-election for another five-year mandate.
"It would betray my conscience to take up a responsibility that requires mobility and total devotion, that I am not in physical condition to offer," Castro wrote.
Al Jazeera's correspondent Gabriel Elizondo reported that, even though Castro's announcement was expected, his resignation is a "final turning over of power".
Speaking from Sao Paulo, Brazil, he said that the iconic revolutionary commander has generally been viewed as a "real leader" in the Americas and carries a prominent legacy with him.
The assembly is likely to nominate Raul, Castro's brother, as president when it meets on February 24. Castro has not appeared in public since 2006.
Castro's retirement brings an end to a political career that survived the Cold war, assassination attempts by the CIA, nine US presidents and the breakup of the Soviet Union.
He came to power in 1959 in a Communist revolution that overthrew the then president Fulgenico Bautista.
He became an icon of socialism and a staunch opponent of the US which led to a crippling political and economic blockade of the Caribbean island.
Al Jazeera's correspondent David Hawkins said the US would welcome the permanent departure from power of Castro, but with Raul in position, relations between the two countries will remain severed.
"Castro is a living piece of history while his brother Raul does not have his same stature," Hawkins said.
Castro is admired in the developing world for standing up to the US, but is accused by his opponents of suppressing freedom.