Tropical forest regions in equatorial Africa are threatened with degradation, deforestation and biodiversity loss as a result of land-cover change. We investigated historical land-cover dynamics in unprotected forested areas of the Littoral Region in south-western Cameroon during 1975–2017, to detect changes that may influence this important biodiversity and wildlife area. Processed Landsat imagery was used to map and monitor changes in land use and land cover. From 1975 to 2017 the area of high-value forest landscapes decreased by c. 420,000 ha, and increasing forest fragmentation caused a decline of c. 12% in the largest patch index. Conversely, disturbed vegetation, cleared areas and urban areas all expanded in extent, by 32% (c. 400,000 ha), 5.6% (c. 26,800 ha) and 6.6% (c. 78,631 ha), respectively. The greatest increase was in the area converted to oil palm plantations (c. 26,893 ha), followed by logging and land clearing (c. 34,838 ha), all of which were the major factors driving deforestation in the study area. Our findings highlight the increasing threats facing the wider Littoral Region, which includes Mount Nlonako and Ebo Forest, both of which are critical areas for regional conservation and the latter a proposed National Park and the only sizable area of intact forest in the region. Intact forest in the Littoral Region, and in particular at Ebo, merits urgent protection.