Successful control of schistosomiasis, a water-borne parasitic disease, is challenged by the intricacy of the worm’s lifecycle, which depends on aquatic snail intermediate hosts, and involves environmental, ecologic, and socio-economic factors. Current strategies rely on deworming through mass drug administration which however do not protect against reinfection and the persistence of hotspots. It is recognized that multifaceted approaches will be necessary to reach elimination, whose development will require a renewed focus on the disease’s social-ecological drivers. Taking cue from the hydrological underpinning of these drivers, this Thesis aims at developing an ecohydrological approach to schistosomiasis with a view to identifying and exploiting the points in which its cycle can be broken. Schistosomiasis is a poverty-reinforcing disease affecting more than 150 million people in sub-Saharan Africa, being the parasitic disease causing the largest health burden after malaria. However, the impairing morbidity it causes has been undervalued in the past, qualifying it as a neglected tropical disease. Moreover, water resources development often exacerbate transmission, posing scientific and ethical challenges in addressing the ensuing trade-off between economic development and public health. The relevance of this Thesis’ work lies in furthering tools to offset this trade-off by unlocking the predictive appraisal of the social-ecological drivers of transmission. An integration of fieldwork applied in Burkina Faso (West Africa) and theoretical methods are employed to address this aim. This Thesis establishes the use of spatially explicit mathematical models of schistosomiasis at the national-scale, allowing to study the effect of human mobility and spatial heterogeneity of transmission parameters. Weekly ecological samplings of snail abundance and continuous environmental monitoring were preformed at three sites along the country’s climatic gradient, leveraged through ecological modelling. A novel methodology for the large-scale prediction of river network ephemerality allowed for refined snail species distribution models, and the analysis of the disease’s geography in link with socio-economic covariates. Finally, surveys and participatory workshops shed light on local-scale water contact patterns. The obtained results substantiate the stance that hydrology is a first-order control of disease transmission. Stability analysis of the spatially explicit model generated additional insight into the impact of the expansion of suitable snail habitat due to water resources development, highlighting the interplay between local and country-wide effects driven by human mobility. Models of snail ecology revealed key hydrological drivers, and disputed density feedbacks. Uncovered phase shifts between permanent and ephemeral habitats were adequately reproduced at the national scale through model regionalization. Characterization and predictions of hydrological ephemerality improved the estimation of the snails’ ecological range, mirroring the disease’s geography. Finally a national-scale association between ephemerality and disease risk was observed, possibly due to human-water contacts aggregation, as supported by preliminary results at village-level. The future incorporation of these ecohydrological findings into spatially explicit models of schistosomiasis is considered promising for optimizing control strategies and attaining disease elimination.