The case unveiled on Wednesday accuses Castro and five others in the shooting down of the aircraft belonging to Cuban-American group Brothers to the Rescue and killing four people, including three Americans.
Castro, now 94, was then head of the country's armed forces and faced international condemnation over the crash.
As the US seeks to exert increasing pressure on Cuba's communist rule, President Miguel Díaz-Canel called the charges "a political manoeuvre, devoid of any legal foundation".
Speaking at Freedom Tower in Miami, Acting Attorney General Todd Blanche announced that the US would also charge Castro with destruction of aircraft, and four individual counts of murder over the deaths of Armando Alejandre Jr, Carlos Alberto Costa, Mario Manuel de la Peña, and Pablo Morales.
