Born near Lisbon in Alexandria, he was for some time known as The Great, and as The Portuguese Mars. Through his father, Gonzalvo, who held an important position at court, he was connected by illegitimate descent with the royal family of Portugal. He was educated at the court of Alfonso V of Portugal, and after the death of that monarch seems to have served for some time in Africa. On his return he was appointed estribeiro-mor (chief equerry) to John II.
In 1503 he set out on his first expedition to the East, which was to be the scene of his future triumphs. In company with his kinsman Francisco he sailed round the Cape of Good Hope to India, and succeeded in establishing the king of Cochin securely on his throne, obtaining in return for this service permission to build a Portuguese fort at Cochin, and thus laying the foundation of his country's empire in the East.
He returned home in July 1504, and was well received by King Manuel I of Portugal, who entrusted him with the command of a squadron of five vessels in the fleet of sixteen which sailed for India in 1506 under Tristao da Cunha. After a series of successful attacks on the Arab cities on the east coast of Africa, Albuquerque separated from Da Cunha, and sailed with his squadron against the island of Ormuz, in the Persian Gulf, which was then one of the chief centres of commerce in the East. He arrived on September 25, 1507, and soon obtained possession of the island, though he was unable long to maintain his position.
With his squadron increased by three vessels, he reached the Malabar coast at the close of the year 1508, and immediately made known the commission he had received from the king empowering him to supersede the governor Francisco de Almeida. The latter, however, refused to recognize Albuquerque's credentials and cast him into prison, from which he was only released, after three months' confinement, on the arrival of the grand-marshal of Portugal with a large fleet. Almeida having returned home, Albuquerque speedily showed the energy and determination of his character.
An unsuccessful attack upon Calicut in January 1510, in which the commander-in-chief received a severe wound, was immediately followed by the investment and capture of Goa. Albuquerque, finding himself unable to hold the town on his first occupation, abandoned it in August, to return with the reinforcements in November, when he obtained undisputed possession. He next directed his forces against Malacca, which he subdued after a severe struggle. He remained in the town nearly a year in order to strengthen the position of the Portuguese power.
In 1512 he sailed for the coast of Malabar. On the voyage a violent storm arose, Albuquerque's vessel, the Flor de la Mar, which carried the treasure he had amassed in his conquests, was wrecked, and he himself barely escaped with his life. In September of the same year he arrived at Goa, where he quickly suppressed a serious revolt headed by Idalcan, and took such measures for the security and peace of the town that it became the most flourishing of the Portuguese settlements in India. Albuquerque had been for some time under orders from the home government to undertake an expedition to the Red Sea, in order to secure that channel of communication exclusively to Portugal. He accordingly laid siege to Aden in 1513, but was repulsed; and a voyage into the Red Sea, the first ever made by a European fleet, led to no substantial results. In order to destroy the power of Egypt, he is said to have entertained the idea of diverting the course of the Nile River and so rendering the whole country barren. His last warlike undertaking was a second attack upon Ormuz in 1515. The island yielded to him without resistance, and it remained in the possession of the Portuguese until 1622.
Albuquerque's career had a painful and ignominious close. He had several enemies at the Portuguese court who lost no opportunity of stirring up the jealousy of king Manuel against him, and his own injudicious and arbitrary conduct on several occasions served their end only too well. On his return from Ormuz, at the entrance of the harbour of Goa, he met a vessel from Europe bearing despatches announcing that he was superseded by his personal enemy Soarez. The blow was too much for him and he died at sea on December 16, 1515. Before his death he wrote a letter to the king in dignified and affecting terms, vindicating his conduct and claiming for his son the honours and rewards that were justly due to himself. His body was buried at Goa in the Church of our Lady, and it is perhaps the most convincing proof possible of the justice of his administration that, many years after, Muslims and Hindus used to go to his tomb to invoke protection against the injustice of his successors. The king of Portugal was convinced too late of his fidelity, and endeavoured to atone for the ingratitude with which he had treated him by heaping honours upon his natural son Alfonso. The latter published a selection from his father's papers under the title Commentarios do Grande Affonso d'Alboquerque.