Juan Manuel de Villena y de la Vega (died 1543) was a Castilian nobleman, third lord of Belmonte, member of the Order of the Golden Fleece, Contador mayor of Castile, reeve of Burgos, Segovia, Plasencia, Jaén and Atienza.
After the death of Philip I of Castile in 1506, a conflict with Ferdinand II of Aragon forced Juan Manuel into exile in Flanders, where he was apprehended and imprisoned.
He was freed by Charles V and made ambassador to Pope Leo X, and in 1523 a position as councillor of state.
His own tomb is there, as well as that of his mother, Aldonza de la Vega, and that of his wife.
His firstborn and heir was Lorenzo Manuel de Villena y Rojas, commander of the Order of Alcántara and senior butler to Charles V. His younger sons were Juan, bishop of Sigüenza (r. 1574–1579), Pedro, Lorenzo and Rodrigo.