Introduction: Schistosomiasis is one of the Neglected Tropical Diseases (NTDs) targeted for elimination in Uganda by 2025 through Mass Drug Administration (MDA) using praziquantel.  To achieve this, WHO estimates indicate that MDA coverage and uptake of 75% is required. However, coverage remains suboptimal with insufficient knowledge and inadequate drug supply often cited as key reasons. There is a need to add to the body of knowledge in various settings to enable more robust mitigation measures. This study aimed to assess the uptake of praziquantel for MDA and associated factors in Butiaba sub-county along the shores of Lake Albert in Uganda. Methods: A cross-sectional study was conducted in five randomly selected villages within Butiaba sub-county between July and September 2021 using quantitative and qualitative approaches. Semi-structured questionnaires were administered to 450 adults, with additional two Focus Group Discussions and Key Informant interviews held with implementation structures from the village to district level. Results: Self-reported uptake of praziquantel within twelve months of the most recent MDA exercise was 71.56% (95% CI: 67.14 – 75.68). Of all the participants, 5.78% reported have never swallowed praziquantel in their lifetime, and 75% (96/128) of participants who didn’t swallow praziquantel in the last twelve months reported having at least swallowed the drug in the last ten years. Respondents were less likely to have swallowed praziquantel if they had no knowledge about schistosomiasis signs (AOR= 0.18, 95% CI: 0.08–0.39) and more likely if they were between the ages 30-39years (AOR= 2.31, 95% CI: 1.35–3.95) or 40 years and above (AOR= 2.86, 95% CI: 1.45 – 4.95). Operational  challenges such as the inadequate supply of praziquantel and financial constraints also influence the uptake of praziquantel during MDA in Butiaba sub-county. Conclusion: The uptake of praziquantel during MDA in Butiaba sub-county was high but still below the WHO target of 75%. People with limited knowledge of schistosomiasis symptoms and those aged 18 – 29 years were less likely to take Praziquantel. Irregular drug supply was also a key challenge. Recommendation: Rigorous health education and ensuring a continuous supply of Praziquantel are key to improving MDA uptake.