Archeology has not sufficiently explained Guinea-Bissau's prehistory. In 1000 BC, there were hunter-gatherers in the area, hundreds of thousands of years after they had traversed the rest of Africa. This was soon followed in the archaeological record by farmers using iron tools.

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Guinea-Bissau was once part of the kingdom of Gabu, part of the Mali Empire in the 16th century. Parts of this kingdom persisted until the 18th century. Other areas of the territory that currently make up the country were considered by the Portuguese as part of their empire.

Guinea-Bissau was known as the Slave Coast, as it was an important area for the export of African slaves by Europeans destined for the Western Hemisphere.

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The first accounts of Europeans arriving in this area include those of the voyage of the Venetian Alvise Cadamosto in 1455, the voyage in 1479-1480 of the Flemish-French merchant Eustache de la Fosse and Diogo Cão. In the 1480s, this Portuguese explorer reached the Congo River and the lands of Bakongo, laying the foundations of modern Angola, some 4200 km off the African coast from Guinea-Bissau.

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Although the rivers and coast of this area were among the first places colonized by the Portuguese, who created trading posts in the 16th century, they did not explore the interior until the 19th century. Local African rulers in Guinea, some of whom prospered greatly from the slave trade, controlled the inland trade and did not allow Europeans to enter the area. African communities fighting slave traders were also suspicious of European adventurers and would-be settlers. The Portuguese in Guinea were largely restricted to the ports of Bissau and Cacheu. A small number of European settlers established isolated farms along Bissau's inland rivers.

​During a brief period in the 1790s, the British attempted to establish a rival base on the island of Bolama. However, in the 19th century, the Portuguese were sufficiently secure in Bissau to also consider the neighboring coast as their territory, the same happening to the north in an area currently belonging to Senegal.

​An armed rebellion, started in 1956, by the African Party for the Independence of Guinea and Cape Verde (PAIGC) under the leadership of Amílcar Cabral gradually consolidated its rule over what was then Portuguese Guinea.  Unlike guerrilla movements in other Portuguese colonies, the PAIGC quickly extended its military control over large portions of the territory, aided by the jungle-like terrain, its easy approach to the border with neighboring allies, and by large amounts of weapons coming from Cuba, China, the Soviet Union, and left-wing African countries. Cuba also agreed to provide artillery experts, doctors and technicians. The PAIGC even managed to acquire significant anti-aircraft capability to defend against air attacks. By 1973, the PAIGC controlled many parts of Guinea, although the movement suffered a setback in January 1973, when Cabral was assassinated.

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Independence was unilaterally declared on September 24, 1973, which is now celebrated as the country's Independence Day, a public holiday. Recognition became universal after the 25th of April 1974, the socialist-inspired military coup in Portugal, which overthrew the Estado Novo in Lisbon. Nicolae Ceaușescu of Romania, was the first to formally recognize Guinea-Bissau and the first to sign agreements with the African Party for the Independence of Guinea and Cape Verde.