BackgroundIn Senegalese high-burden regions, the existing package of interventions is insufficient to reach the malaria elimination goal. Asymptomatic carriers of Plasmodium contribute significantly to malaria persistence and are not targeted by current interventions. The systematic treatment of all individuals in a community (mass drug administration, MDA) is a relevant intervention to tackle asymptomatic infections. The intervention can only be effective with a high participation of the population and, therefore, depends largely on its acceptability. This study aims to investigate the prospective acceptability of MDA in the Kedougou region to inform its potential use in a future strategy.MethodsFollowing a 7-construct theoretical framework, prospective acceptability of MDA implemented in the rainy season was studied. In four villages, a sequential mixed design, from qualitative to quantitative, was used. In November 2021, interviews with healthcare professionals and focus groups with villagers were conducted. Findings from thematic analysis informed the development of a questionnaire administered to individuals aged ≥ 15 years in March 2022. Based on the questionnaire, an acceptability score was constructed and associations with socio-demographic factors were investigated using a linear mixed model.ResultsThe 7 interviews, the 12 focus groups, and the questionnaire administered to 289 individuals demonstrated a good acceptability of MDA. Two potential barriers were identified: the contradiction of taking a medication without feeling sick and the occurrence of side effects; and four facilitators: the perception of malaria as a burden, a good understanding of MDA, a good perceived effectiveness, and the resulting economic benefits. The average acceptability score was 3.5 (range from -7 to + 7). Young adults aged 15 to 21 had a lower acceptability score compared to the other age groups, indicating an additional barrier to acceptability (β = -0.78 [-1.67;0.1]).ConclusionMDA is a priori acceptable to communities of Kedougou region in Senegal. Sensitization campaigns co-constructed with the communities, especially targeting young adults, are essential to ensure good acceptability.