A member of the House of Aviz, Manuel was Duke of Beja and Viseu prior to succeeding his cousin, John II of Portugal, as monarch.

Manuel established the Casa da Índia, a royal institution that managed Portugal's monopolies and its imperial expansion.

[9] In 1483, Fernando II, Duke of Braganza, leader of Portugal's most powerful feudal house,[10] was executed for treason.

[11][12] Later, Manuel's older brother, Diogo, Duke of Viseu, was accused of leading a conspiracy against the crown and was stabbed to death in 1484 by the king himself.

[17] 1505 – The construction of forts at Kilwa, Sofala, Angediva, and Cannanore by Francisco de Almeida as the first viceroy of India.

[26] All these events made Portugal wealthy from foreign trade as it formally established a vast overseas empire.

He reformed the courts of justice and the municipal charters with the crown, modernizing taxes and the concepts of tributes and rights.

Afterwards, all converted Jews and their descendants would be referred to as "New Christians" and were given a grace period of thirty years in which no inquiries into their faith would be allowed, which was later extended to end in 1534.

[34][48] In addition, Manuel also ordered the expulsion of Muslims from Portugal, and he is known to have pressured Ferdinand and Isabella of Spain to end the toleration of Islam in their own kingdom.

[40] Isabella died in childbirth,[49] thus putting a damper on Portuguese ambitions to rule in Spain, which various rulers had harbored since the reign of King Ferdinand I (1367–1383).

[citation needed] In December 1521, while Lisbon was dealing with an outbreak of the Black Plague, Manuel and his court remained at Ribeira Palace.

[56][57] The next day, his body was transported to the Belém district of Lisbon, in a black velvet-draped coffin, followed by masses of mourners.

He was provisionally buried at Restelo Church, while the royal pantheon of the House of Aviz was furnished inside Jerónimos Monastery.