The treatment and control of schistosomiasis, a neglected disease that affects more than 200 million people worldwide, rely on the use of a single drug, praziquantel. A vaccine has yet to be developed, and since new drug design and development is a lengthy and costly process, drug repurposing is a promising strategy. In this study, the efficacy of promethazine, a first-generation antihistamine, was evaluated against Schistosoma mansoni ex vivo and in a murine model of schistosomiasis.