The COVID-19 epidemic has shown regional variations in transmission and outcomes. As a primary hotspot in Chad, N'Djamena is crucial for comprehensive epidemiological investigation. Our study employed two methodologies: seroprevalence data collection and whole-genome sequencing of SARS-CoV-2 strains. This dual approach assessed population exposure and virus genetic diversity. Seroprevalence data indicated broader exposure than confirmed cases suggested, and genome sequencing identified multiple strains, including globally recognized variants of concern. Integrating these data provided insights into transmission dynamics, potential herd immunity thresholds, and the impact of specific variants on disease progression. Our findings underscore the importance of integrated, multidisciplinary research in infectious disease epidemiology and inform targeted public health strategies, including social measures and vaccination, to combat infectious diseases in N'Djamena.