The island was inhabited in the middle of the first millennium BC by Bantu tribes from the mainland, who formed the Bubi ethnic group.

The Portuguese developed the island for sugarcane crops, and while considered poor quality, the refineries' output was such that Fernando Po sugar briefly dominated the trade centres in Europe.

[citation needed] In 1642, the Dutch East India Company established trade bases on the island without Portuguese consent.

During a period when enslavement was increasing in the region, local clans abandoned their coastal settlements and settled in the safer hinterland.

The treaty was signed by Queen Mary I of Portugal and King Charles III of Spain, in exchange for territory on the American continent.

Spain mounted an expedition to Fernando Po, led by the Conde de Argelejos, who stayed for four months.

[12] In March 1843, Juan José Lerena planted the Spanish flag in Port Clarence (renamed Santa Isabel), starting the decline of British influence on the island.

[13] Madabita (1842–1860) and Sepoko (1860–1875) were principal local chiefs during the period when Spain re-established its control of the island.

This period was also marked by Spain's transport deportation here of several hundred Afro-Cubans, as well as dozens of Spanish scholars and politicians considered politically undesirable.

[14]: 539 In 1923–1930, the League of Nations investigated the transportation of contract migrant labour between Liberia and the Spanish colony of Fernando Po.

Although the League concentrated its attention on arrangements in Liberia, a closer examination revealed that labour abuse arose from conditions on Fernando Po.

In the last quarter of the 19th century, Krio planters on the island had shifted from palm oil trading to cocoa cultivation.

Their dependence on migrant labour and increasing competition with Europeans resulted in an economic crisis in the first years of the twentieth century.

Planters detained labour but failed to pay their contracts, resulting in a situation of de facto slavery.

[15] In 1942 Fernando Po was the scene of a secretive small scale British raid code named Operation Postmaster which was an action that sought to disrupt German U-boat resupply activities being conducted on the island.

During the Nigerian Civil War in the 20th century, relief agencies used the island as one of the bases for Biafran airlift flights into the secessionist Republic of Biafra.

Tourist attractions include the colonial quarter in Malabo, and the southern part of the island, where visitors can hike to the Iladyi Cascades [es] (Moka Falls) and to remote beaches of Ureka to watch nesting turtles.