Afonso de Albuquerque was born in 1453 in Alhandra, near Lisbon. He was the second son of Goncalo de Albuquerque, Lord of Vila Verde dos Francos, and Dona Leonor de Menezes. His father held an important position at court and was connected by remote illegitimate descent with the Portuguese monarchy. He was educated in mathematics and Latin at the court of Afonso V of Portugal, where he befriended Prince John, the future King John II of Portugal.

The fleet left Lisbon on 6 April 1506. Afonso piloted his ship himself, having lost his appointed pilot on departure. In Mozambique Channel, they rescued Captain Joao da Nova, who had encountered difficulties on his return from India; da Nova and his ship, the Frol de la mar, joined da Cunha's fleet. From Malindi, da Cunha sent envoys to Ethiopia, which at the time was thought to be closer than it actually is. Those included the priest Joao Gomes, Joao Sanches and Tunisian Sid Mohammed who, having failed to cross the region, headed for Socotra; from there, Afonso managed to land them in Filuk. After successful attacks on Arab cities on the east Africa coast, they conquered Socotra and built a fortress at Suq, hoping to establish a base to stop the Red Sea commerce to the Indian Ocean. However, Socotra was abandoned four years later, as it was not advantageous as a base.  At Socotra, they parted ways: Tristao da Cunha sailed for India, where he would relieve the Portuguese besieged at Cannanore, while Afonso took seven ships and 500 men to Ormuz in the Persian Gulf, one of the chief eastern centers of commerce. On his way, he conquered the cities of Curiati (Kuryat), Muscat in July 1507, and Khor Fakkan, accepting the submission of the cities of Kalhat and Sohar. He arrived at Ormuz on 25 September and soon captured the city, which agreed to become a tributary state of the Portuguese king.  Hormuz was then a tributary state of Shah Ismail of Persia. In a famous episode, shortly after it's conquest Albuquerque was confronted by Persian envoys, who demanded the payment of the due tribute from him instead. He ordered them be given a stock of cannonballs, arrows and weapons, retorting that "such was the currency struck in Portugal to pay the tribute demanded from the dominions of King Manuel"  According to Bras de Albuquerque, it was Shah Ismael who coined the term "Lion of the seas", addressing Albuquerque as such. Afonso began building the Fort of Our Lady of Victory (later renamed Fort of Our Lady of the Conception), engaging his men of all ranks in the work.  However, some of his officers revolted against the heavy work and climate and, claiming that Afonso was exceeding his orders, departed for India. With the fleet reduced to two ships and left without supplies, he was unable to maintain this position for long. Forced to abandon Ormuz in January 1508, he raided coastal villages to resupply the settlement of Socotra, returned to Ormuz, and then headed to India.

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