ABSTRACT Background The sero‐epidemiological characteristics of SARS‐CoV‐2 infections in Mali are not yet well understood. This study assessed SARS‐CoV‐2 antibody seroprevalence and factors associated with antibody responses in the general population of Bamako, the capital city and epicenter of COVID‐19, to assess the magnitude of the pandemic and contribute to control strategy improvements in Mali. Methods A cross‐sectional survey was conducted in September 2022 to collect sociodemographic information, clinical characteristics, comorbid factors, and blood samples. ELISA was performed to determine anti‐Spike (anti‐S) and anti‐RBD antibody levels. A total of 3601 participants were enrolled in REDCap. R‐Studio was used for the statistical analysis. The chi‐squared (χ2) test was used to compare the proportions across different groups. Logistic regression models were used to elucidate factors associated with antibody responses. Result The sex ratio for female‐to‐male was 3.6:1. The most representative groups were the 20–29‐year‐olds (28.9%, n = 1043) and the 30–39‐year‐olds (26.9%, n = 967). The COVID‐19 vaccine coverage among the participants was 35.8%, with vaccines from Covishield AstraZeneca (13.4%), Johnson & Johnson (16.7%), Sinovac (3.9%), and BioNTech Pfizer (1.8%). Overall, S protein and RBD antibody seroprevalences were remarkably high in the study population (98% and 97%, respectively). Factors such as youth (1–9 years old) and male sex were associated with lower SARS‐CoV‐2 antibody responses, whereas COVID‐19 vaccinations were associated with increased antibody responses. Conclusion This serosurvey demonstrated the high seroprevalence of SARS‐CoV‐2 antibodies and highlighted the factors influencing antibody responses, while clearly underlining an underestimation of the pandemic in Mali.