His death is reportedly the first time in 40 years that a Cuban political prisoner has succumbed during a hunger protest.
The news was first carried on Cuban exile radio stations based in southern Florida, which broadcast an interview with his mother, Reina Luisa Tamayo.
"We can consider it a judicial assassination," Elizardo Sanchez, head of the Havana-based independent Cuban Commission on Human Rights and National Reconciliation, was quoted as saying in UNFree Media Americas, a blog by local journalists.
Zapata Tamayo was arrested in 2003 on charges of disrespecting authority and sentenced to three years in jail.
"The dissident's condition and fate are the Castro brothers' doing. The murder by the tyrant Fidel Castro and his cowardly jailers will never be forgotten"
The term was later extended to 25 years, partly due to his political activism while behind bars said Sanchez
He added that Zapata Tamayo's family first announced last week that prison doctors had told them he was gravely ill.
Hours after the news spread several US legislators issued separate statements blaming the Cuban leadership for the activist's death.
Lincoln Diaz-Balart, a Republican from Florida and the nephew of the ex-wife of Fidel Castro, Cuba's former president, said in the US congress that the dissident's "condition and fate are the Castro brothers' doing".
He later declared that the "murder by the tyrant Fidel Castro and his cowardly jailers will never be forgotten".
Bill Nelson, a Florida senator, said "freedom-loving people everywhere should hold the Cuban regime responsible for the fate of Orlando Zapata Tamayo".
"His reported death today is a sad reminder of the tragic cost of oppression and a dictatorship that devalues human life," he added.
Kendrick Meek, a Democratic legislator from Florida, said: "The Cuban government's stunning lack of respect for human rights was highlighted by Orlando as much in his life as in his death."