Having discovered the sea route to India, Manuel organized successive fleets to that region in order to establish Portuguese commercial hegemony. In 1505 Francisco de Almeida left Lisbon with a fleet of 22 ships and 2,500 men, 1,500 of whom were soldiers. Invested with the title of viceroy of India, Almeida was instructed to conclude alliances with Indian rulers, set up factories, and build forts on the east coast of Africa, which he did at Mombasa and at Kilwa in present-day Tanzania before arriving in India. After his arrival, he fortified the island of Angediva and Cochin. He imposed a system of licenses on trading vessels that threatened to ruin the Muslim traders, who reacted by seeking spices in Malacca in present-day Malaysia and the Sunda Islands in the Malay Archipelago and sailing directly to the Persian Gulf, bypassing India.

Almeida sought to suppress this trade and secure Portuguese commercial hegemony. He was joined in this effort by two more fleets sent from Lisbon, one under the command of Tristão da Cunha and the other under Afonso de Albuquerque, who had been appointed Almeida's successor as viceroy. Cunha explored Madagascar and the coast of east Africa, occupied the island of Socotra (now part of Yemen), and built a fort at the mouth of the Red Sea, before sailing to India. Albuquerque ravaged the Oman coast and attacked Ormuz, the great entrepôt at the mouth of the Persian Gulf, where he began constructing a fort.

The activities of the Portuguese motivated the Muslims to take military action. The sultan of Egypt, allied with the Venetians and Turks, organized a large armada that crossed the Indian Ocean to Diu, where it was engaged by a Portuguese fleet. On February 2, 1509, a great sea battle was fought and the sultan's armada destroyed. This victory assured Portuguese commercial and military hegemony over India and allowed Portugal to extend its empire to the Far East.

Albuquerque established his capital at Goa, which he attacked and occupied in 1510. In 1511 he departed for the conquest of Malacca, the emporium for the spice trade and trade with China, which he accomplished in August of that year. After returning to Goa, Albuquerque made plans to occupy strategic positions in the Persian Gulf and Red Sea. On his first expedition, he failed to take Aden and returned to Goa. His second expedition, which was to be his last, attempted to reduce Ormuz and Aden, as well as conquer Mecca. During this expedition, Albuquerque fell ill and returned to Goa, where he died in 1515.

When Manuel I died in 1521, his son and heir, João III, sent expeditions to the islands of Celebes, Borneo, Java, and Timor, all part of the Malay Archipelago. Relations were established with Japan after the visits of Francisco Xavier and Fernão Mendes Pinto in 1549. Portuguese captains founded factories in China and took possession of Macau in 1557.

Data as of January 1993