His father was Don Nicolás del Castillo, a native of Alicante, and his mother, Doña Manuela Rada, of aristocratic lineage.
In January 1812, Manuel del Castillo joined Commander Joaquín París Ricaurte to submit the province of El Socorro to Cundinamarca.
Castillo was then appointed by Congress as commander of the Province of Pamplona and head of the army vanguard in order to protect the Union from the Royalist forces in Venezuela.
In March 1815, Simón Bolívar was advancing to take Santa Marta and requested extra men and supplies from Cartagena, but Manuel del Castillo refused to support him.
Manuel del Castillo led the defense of Cartagena until October, when a conspiracy of José Francisco Bermúdez, Mariano Montilla and Louis-Michel Aury deposed him from military command and placed him under arrest.