Despite efforts by the Volta River Authority (VRA) to provide services for schistosomiasis control in communities along Ghana’s Volta Basin, high rates of transmission and re-infection persist in the region. To strengthen intervention effectiveness, the VRA partnered with the University of Health and Allied Sciences to conduct implementation research aimed at developing context-specific, evidence-based quality improvement strategies. This mixed-method study evaluates the reach, effectiveness, adoption, implementation, and maintenance of the VRA’s quality improvement intervention for their mass drug administration (MDA) for schistosomiasis. Baseline and endline surveys were analysed using STATA and qualitative data from in-depth interviews (IDIs) and focus group discussions (FGDs) were coded and analysed thematically using Taguette. Urogenital schistosomiasis prevalence decreased by 87.83% in Shai Osudoku, 88.98% in South Tongu, and 90.96% in Asuogyaman after the intervention. The findings revealed high training levels among district health management staff and community drug distributors, high health worker satisfaction with the training, and positive community reception of the intervention. However, praziquantel side effects and related opportunity costs may have posed a barrier to drug uptake. Moreover, re-infection remains a challenge, which could be attributed to high domestic and economic reliance on the Volta River.