Mesenchymal stem cells (MSCs) have gained popularity for their potential as seed cells to treat various human diseases, including pathogenic infections. Schistosoma japonicum (S. japonicum) infection is characterized by formation of parasite egg granulomas and host liver fibrosis. MSCs have been proposed as useful treatments of S. japonicum infection, but the efficacy and underlying mechanisms remain unknown. Herein, we report that MSCs were able to ameliorate S. japonicum-induced liver injury in vivo and this effect was enhanced by combining MSCs with conventional drug praziquantel (PZQ). Kunming strains of mice were infected with S. japonicum and treated with vehicle, MSCs, PZQ or PZQ + MSCs. MSC treatment not only prolonged the survival time of infected mice but reduced egg granuloma diameter and decreased the concentrations of serum transforming growth factor-β1 and hyaluronic acid. MSC treatment also inhibited collagen deposition and reduced the expression of collagen type 3, α-smooth muscle actin and vimentin in infected mouse liver tissues. Collectively, our findings suggest that MSC treatment represents a novel therapeutic approach for S. japonicum-induced liver injury and fibrosis.