Very little is known about Vasco da Gama before his appointment as "Capitão Mor" (Captain-General) of the fleet sent to find the sea route to India. Vasco da Gama was born circa 1469 at Sines as the son of Estêvão da Gama - a knight commander of Cercal of the Order of St. James of the Sword, - and of his wife Isabel Sodré.

His father's family, from the southern province of Alentejo, appears to have had close links with the military Order of Avis and later on with the Order of St. James. His mother's family, of English ascendancy, had also links with Dom Diogo, duke of Viseu and governor of the military Order of Christ.

After the return of Bartolomeu Dias, Estevão da Gama was chosen by João II to command the next expedition of discovery, but, as both died before the project could be carried into execution, the new king Manuel I commissioned Vasco da Gama, who had already distinguished himself at the beginning of the year 1490 by defending the Portuguese colonies on the coast of Guinea against French encroachments.

Pedro de Corvilhão on his land way from India had descended the east coast of Africa as far as the twentieth degree of south latitude, and had become cognizant of the old Arabic-Indian commercial association. It remained for an expedition to prove the link between the findings of Dias and those of da Covilhã and de Paiva and to connect these separate segments into a potentially lucrative trade route into the Indian Ocean. The nautical problem, therefore, to be solved by Vasco da Gama was clearly outlined, and the course for the sea route to the East Indies designated.

In January, 1497, the command of the expedition was solemnly conferred upon Vasco da Gama, and on 8 July, 1497, the fleet of four ships with a total crew of about one hundred and fifty men, sailed from Lisbon under the leadership of Vasco, his brother Paulo, and Nicoláo Coelho.
They followed the route pioneered by earlier explorers along the coast of Africa via Tenerife and the Cape Verde Islands. After reaching the coast of present day Sierra Leone, da Gama took a course south into the open ocean, crossing the Equator and seeking the South Atlantic westerlies that Bartolomeu Dias had discovered in 1487. This course proved successful and on November 4, 1497, the expedition made landfall on the south African coast. For over three months the ships had sailed more than 6,000 miles of open ocean, by far the longest journey out of sight of land made by the time.
After their landfall in south Africa they had to refill provisions and anchored in St. Helena Bay and in Mossel Bay rounding the south-most point of the African continent. On 16 December, the fleet arrived at the furthest landing point of Dias. With Christmas pending, da Gama and his crew gave the coast they were passing the name Natal. By the end of January, 1498, the expedition reached the month of the Zambezi, which was in the territory controlled by the Arabian maritime commercial association.

Menanced by the Arabs in Mozambique and Mombasa, who feared to loose the supremacy in their Indian Ocean commerce, they were on the contrary, received in a friendly manner at Malindi, East Africa on 14 April. Da Gama and his crew contracted the services of a pilot whose knowledge of the monsoon winds allowed him to bring the expedition the rest of the way to Calicut, located on the southwest coast of India. They reached Kozhikkode (Calicut) on 20 May 1498. Calicut had been the principal market for trade in spices, precious stones, and pearls since many centuries. Muslim Arab merchants traded with Calicut as early as 7th century, and the strong colony of Arab merchants settled in Calicut was hostile to Vasco da Gama's expedition, but the Zamorin welcomed the Portuguese and allowed them to take pepper, drugs etc., on board. Zamorin was the royal title used by the Hindu Nair kings of Calicut, which was one of the larger feudal kingdoms in late medieval India. Despite the Arab opposition, Gama succeeded in obtaining a permission to carry out trade, but failed in establishing a permanent trading colony in Calicut.

Vasco da Gama left Calicut on 29 August 1498. Eager to set sail for home, he ignored the local knowledge of monsoon wind patterns which were still blowing onshore. The fleet initially inched north along the Indian coast, and then anchored in at Anjediva island for a spell. They finally struck out for their Indian Ocean crossing on 3 October, 1498. But with the winter monsoon yet to set in, it was a harrowing journey. On the outgoing journey, sailing with the summer monsoon wind, it had taken Gama's fleet only 23 days to cross the Indian Ocean; now, on the return trip, sailing against the wind, it took 132 days. Vasco da Gama's fleet finally arrived in Malindi on 7 January 1499, in a terrible shape - approximately half of the crew had died during the crossing, and many of the rest were afflicted with scurvy. Not having enough crewmen left standing to manage three ships, Vasco da Gama ordered to scuttle off one ship on the East African coast, and to re-distributed the crew to the two remaining two ships, the São Gabriel and the Berrio. Thereafter, the sailing was smoother. By early March, they had arrived in Mossel Bay, and crossed the Cape of Good Hope in the opposite direction on March 20. They reached the west African coast by April 25.

They continued to Cape Verde, where Nicolau Coelho's Berrio separated from Vasco da Gama's São Gabriel, and sailed on by itself. Coelho arrived in Portugal on 10 July, 1499. In the meantime, back in Cape Verde, Vasco's brother, Paulo da Gama had fallen grievously ill. Gama elected to stay by his side on Santiago island, and handed the São Gabriel over to his clerk, João de Sá, to take home. The Sá arrived in Lisbon sometime in late July or early August. Vasco da Gama and his sickly brother eventually sailed with a Guinea caravel returning to Portugal, but Paulo da Gama died en route. Vasco da Gama got off at the Azores to bury his brother and eventually took passage on an Azorean caravel arriving in Lisbon on August 29, 1499. He was appointed to the newly created post of Admiral of the Indian Ocean, which was rewarded with a high salary.

The expedition had demanded a large cost - two ships and over half the men had been lost. It had also failed in its principal mission of securing a commercial treaty with Calicut. Nonetheless, the spices brought back on the remaining two ships were sold at an enormous profit to the crown. Vasco da Gama was celebrated for opening a direct sea route to Asia. His path would be followed up thereafter by yearly Portuguese "India Armadas".
The spice trade would prove to be a major asset to the Portuguese royal treasury, and other consequences soon followed. For example, Gama's voyage had made it clear that the east coast of Africa, the Contra Costa, was essential to Portuguese interests. Its ports provided fresh water, provisions, timber, and harbours for repairs, and served as a refuge where ships could wait out unfavourable weather. One significant result was the colonization of Mozambique by the Portuguese Crown.

The follow-up expedition, the "Second India Armada" launched in 1500, was placed under the command of Pedro Álvares Cabral, with the mission of making a treaty with the Zamorin of Calicut and setting up a Portuguese factory in the city. However, Cabral entered into a conflict with the local Arab merchant guilds, with the result that the Portuguese factory was overrun in a riot and up to 70 Portuguese killed. Cabral blamed the Zamorin for the incident and bombarded the city. Thus war broke out between Portugal and Calicut.

By royal appointment, Vasco da Gama was put to command of the "Fourth India Armada", scheduled to set out in 1502, with the goal of taking revenge upon the Zamorin and force him to submit to Portuguese terms. The first two squadrons of the heavily-armed fleet of fifteen ships and eight hundred men left Lisbon on 12 February 1502. One of the squadrons was led by his uncles, Vicente Sodré. A third squadron - five ships under Gama's cousin Estêvão da Gama - sets out from Lisbon about two months later. Charting its own course, this third squadron will catch up with the main body of the "Fourth Armada" in India. Violent storms at the Cape separates the fifteen ships of Vasco da Gama's fleet. Each captain is forced to figure out his own passage around the Cape, and make his own way towards the pre-arranged rendez-vous point at Mozambique Island where the fleet will stop for repairs and refilling supplies. Also Estêvão da Gama's fleet is caught in a terrible storm around the Cape and split into two groups.

On reaching India in October 1502, da Gama started capturing any Arab vessel he came across in Indian waters, most infamous the capturing of the Miri, a pilgrim ship from Mecca, whose passengers he had massacred in open water. He then appeared before Calicut, demanding redress for the treatment meted out to Cabral. While the Zamorin was willing to sign a new treaty, Gama made a preposterous call to the Hindu king to expel all Muslims from Calicut before beginning negotiations, which was naturally turned down. The Portuguese fleet then bombarded the city for nearly two days from the sea shore. He also captured several rice vessels and barbarously cut off the crew's hands, ears and noses, dispatching them with an insulting note to the Zamorin.
The violent treatment meted out by Gama quickly brought trade along the Malabar coast of India, upon which Calicut depended, to a standstill. But the Zamorin refused to submit to Portuguese terms, and even ventured to hire a fleet of strong corsair warships to challenge Gama's armada, but which Gama managed to defeat in a naval battle before Calicut harbor. Finally, Gama loaded up with spices at Cochin and Cannanore, small nearby kingdoms, half-vassal and half-at-war with the Zamorin, whose alliances had been secured by prior Portuguese fleets. The "Fourth Armada" left India in early 1503.
Gama left behind a small squadron of caravels, under the command of his uncle, Vicente Sodré, to patrol the Indian coast, continue harassing Calicut shipping and protect the newly established Portuguese factories at Cochin and Cannanore from the Zamorin's inevitable reprisals. Vasco da Gama arrived back in Portugal in September 1503, effectively having failed in his mission to bring the Zamorin to submission.

For the next two decades, Vasco da Gama lived out a quiet life, unwelcome in the royal court and sidelined from Indian affairs. His attempts to return to the favor of Manuel I yielded little. Almeida, Albuquerque and Albergaria were the king's new point men for India. But after Ferdinand Magellan defected to the Crown of Castile in 1518, Vasco da Gama threatened to do the same, prompting the king to undertake steps to retain him in Portugal and avoid the embarrassment of losing his own "Admiral of the Seas of India" to Spain.

In 1519, after years of ignoring his petitions, King Manuel I finally hurried to give Vasco da Gama a feudal title, appointing him the first Count of Vidigueira, a count title created by a royal decree issued in &Eecute;vora on December 29, after a complicated agreement with Dom Jaime, Duke of Braganza, who ceded him on payment the towns of Vidigueira and Vila dos Frades. This decree granted Vasco da Gama and his heirs all the revenues and privileges related, thus establishing da Gama as the first Portuguese count who was not born with royal blood.

After the death of King Manuel I in late 1521, his son and successor, King John III of Portugal set about reviewing the Portuguese government overseas. Turning away from the Albuquerque clique, represented by Diogo Lopes de Sequeira, John III looked for a fresh start. Vasco da Gama re-emerged from his political wilderness as an important advisor to the new king's appointments and strategy. Seeing the new Spanish threat to the Moluccas as the priority, Vasco da Gama advised against the obsession with Arabia that had pervaded much of the Manueline period, and continued to be the dominant concern of Duarte de Menezes, then-governor of Portuguese India. Menezes also turned out to be incompetent and corrupt, subject to numerous complaints. As a result, John III decided to appoint Vasco da Gama himself to replace Menezes, confident that the magic of his name and memory of his deeds might better impress his authority, and manage the transition to a new government and new strategy.

By his appointment letter of February 1524, John III granted Vasco da Gama the privileged title of "Viceroy", being only the second Portuguese governor to enjoy that title (the first was Francisco de Almeida in 1505). His second son, Estêvão da Gama was simultaneously appointed "Capitão Mor" do Mar da Índia, to replace Duarte's brother, Luís de Menezes. As a final condition, Gama secured from John III of Portugal the commitment to appoint all his sons successively as Portuguese captains of Malacca.

Setting out in April 1524, with a fleet of fourteen ships, Vasco da Gama took as his flagship the famous large carrack Santa Catarina do Monte Sinai on her last journey to India, along with two of his sons, Estêvão and Paulo. After a troubled journey - four or five of the ships were lost en route - he arrived in India in September.

Vasco da Gama immediately invoked his high vice-regent powers to impose a new order in Portuguese India, replacing all the old officials with his own appointments. But Gama contracted malaria not long after arriving, and died in the city of Cochin on Christmas Eve in 1524, three months after his arrival. As per royal instructions, Gama was succeeded as governor of India by one the captains who had come with him, Henrique de Menezes. Vasco's sons Estêvão and Paulo immediately lost their posts and joined the returning fleet of early 1525.

Vasco da Gama's body was first buried at St. Francis Church, which was located at Fort Kochi in the city of Kochi, but his remains were returned to Portugal in 1539. The body of Vasco da Gama was re-interred in Vidigueira in a casket decorated with gold and jewels.