The area around the Comoé National Park was historically always sparsely populated. Most likely due to the relative barenness of the soil, the presence of the river blindness disease around the Comoé river and the high density of Tsetse flies, which is a vector for sleeping sickness.
In 1926 the area between the Comoé River and Bouna was declared "Refuge Nord de la Côte d'Ivoire", which was enlarged later in 1942 and 53 to "Réserve de Faune de Bouna", giving it some rudimentary protection. The area west of the Comoé river was added to the property on the 9th of February 1968 combined with an elevation to National Park status with an area of 11,500 square kilometres (4,400 sq mi), making it one of the 15 largest National Parks in the World and the largest in West Africa. In 1983 the park was pronounced a biosphere reserve and a UNESCO World Heritage site, due to its unique biodiversity.
After the outbreak of the first Ivorian civil war the park was listed as a World Heritage Site in Danger in 2003, due to absence of management leading to poaching and overgrazing of the park by cattle. During the time between the two civil wars the park suffered greatly under intensive poaching. After the end of the Second Ivorian Civil War the park was able to recover again with the presence of the OIPR (park management) and the re-inauguration of the research station.