BACKGROUND: Schistosomiasis affects nearly 220 million people worldwide, mainly in Sub-Saharan Africa (SSA). Preventive chemotherapy (PC) treatment, through regular mass-drug administration (MDA) of Praziquantel tablets remains the control measure of choice by Ministries of Health. Current guidelines recommend that 75% of school-aged children receive treatment. Many programmes, however, struggle to achieve this target. Given the risk of high reinfection rates, attaining sustained high levels of treatment coverage is essential. This study provides a comprehensive review of the barriers and facilitators operating at different levels of analysis, from the individual to the policy level, conditioning the uptake of PC for schistosomiasis in SSA. METHODOLOGY/PRINCIPAL FINDINGS: A systematic literature search was conducted in several databases for publications released between January 2002 and 2019 that examined factors conditioning the uptake of Praziquantel in the context of MDA campaigns in SSA. A total of 2,258 unique abstracts were identified, of which 65 were selected for full text review and 30 met all eligibility criteria. Joanna Briggs Institute's Critical Appraisal and the Mixed-Methods Assessment tools were used to assess the strength of the evidence. This review was registered with PROSPERO (CRD42017058525). A meta-synthesis approach was used. Results indicated publication bias, with the literature focusing on East African rural settings and evidence at the individual and programmatic levels. The main influencing factors identified included material wellbeing, drug properties, knowledge and attitudes towards schistosomiasis and MDAs, fears of side effects, gender values, community and health systems support, alongside programme design features, like training, sensitisation, and provision of incentives for drug-distributors. The effect of these factors on determining Praziquantel uptake were explored in detail. CONCLUSIONS/SIGNIFICANCE: Multiple determinants of treatment uptake were found in each level of analysis examined. Some of them interact with each other, thus affecting outcomes directly and indirectly. The promotion of context-based transdisciplinary research on the complex dynamics of treatment uptake is not only desirable, but essential, to design effective strategies to attain high levels of treatment coverage.