Zoonotic spillover and hybridization of parasites are major emerging public and veterinary health concerns at the interface of infectious disease biology, evolution and control. Schistosomiasis is a neglected tropical disease of global importance caused by parasites of the Schistosoma genus, and the Schistosoma spp. system within Africa represents a key example of a system where spillover of animal parasites into human populations has enabled formation of hybrids. Combining model-based approaches and analyses of parasitological, molecular and epidemiological data from Northern Senegal, a region with a high prevalence of schistosome hybrids, we aimed to unravel the transmission dynamics of this complex multi-host, multi-parasite system. Using Bayesian methods and by estimating the basic reproduction number (R0), we evaluate the frequency of zoonotic spillover of Schistosoma bovis from livestock, and the potential for onward transmission of hybrid S. bovis×S. haematobium offspring within human populations. We estimate R0 of hybrid schistosomes to be greater than the critical threshold of one (1.76; 95% confidence intervals 1.59-1.99), demonstrating the potential for hybridization to facilitate spread and establishment of schistosomiasis beyond its original geographical boundaries. Equally vital to evaluating multi-host systems is the identification of key hosts; we estimate R0 for S. bovis to be greater than one in cattle (1.43; 95% confidence intervals 1.24-1.85), but not in other ruminants, confirming cattle as the primary zoonotic reservoir. Through longitudinal simulations we also show that where S. bovis and S. haematobium are co-endemic in livestock and humans respectively, the relative importance of zoonotic transmission is predicted to increase as the disease in humans nears elimination.