In 1503, the Count married Juana Enríquez, Lady of la Vega and Ruy Ponce, who died the same year. In 1504 he married for a second time with Juana de Cabrera y Bobadilla, daughter of Andrés de Cabrera, 1st Marquis of Moya, with whom he had three children. In 1506 he married for a third time with María de Luna y Bobadilla, daughter of Alvaro de Luna, 2nd Lord of Fuentidueña.
By Juana de Cabrera:
Pedro Fernández Manrique, 4th Count de Osorno (1504–1569)
Alonso Manrique de Lara
Juan Manrique
By María de Luna:
María Magdalena Manrique, married Andrés Hurtado de Mendoza, 3rd Marquis of Cañete
Diego Hurtado de Mendoza, 4th Marquis of Cañete
García Hurtado de Mendoza, 5th Marquis of Cañete
Isabel de Luna