Manuel was born c. 1516 in Évora to Joana de Vilhena and Dom Francisco of Portugal (1485–1549), 1st Count of Vimioso. He received the title of Comendador of Vimioso and of São Pedro de Calvelo, and was highly regarded by John Manuel, Prince of Portugal, father of the future king Sebastian of Portugal. During his reign, Sebastian appointed him Ambassador of Portugal in Castile. After the unfortunate death of King Sebastian at the Battle of Alcácer Quibir, Dom Manuel took the side of Dom António, Prior of Crato in the succession crisis that followed.