The extent of SARS-CoV-2 circulation in many African countries remains unclear, underlining the need for antibody sero-surveys to assess the cumulative attack rate. Here, we present the results of a cross-sectional sero-survey of a random sample of residents of a health district in Yaounde, Cameroon, conducted from October 14 to November 26, 2020. Among the 971 participants, the test-adjusted seroprevalence of anti-SARS-CoV-2 IgG antibodies was 29·2% (95% CI 24·3–34·1). This is about 322 times greater than the 0.09% nationwide attack rate implied by COVID-19 case counts at the time. Men, obese individuals and those living in large households were significantly more likely to be seropositive, and the majority (64·2% [58·7–69·4]) of seropositive individuals reported no symptoms. Despite the high seroprevalence, most of the population had not been infected with SARS-CoV-2, highlighting the importance of continued measures to control viral spread and quick vaccine deployment to protect the vulnerable.