Praziquantel (PZQ) is an anthelmintic drug, being the first choice for the treatment of schistosomiasis. Its high hydrophobic character and its low water solubility are the main limitations to the development of liquid formulations for the oral administration of the drug. The aim of this work was to develop Solid Lipid Nanoparticles (SLN) for the loading of PZQ for the treatment of S. mansoni infections. PZQ-SLN were produced by hot high shear homogenization. The obtained SLN exhibited a mean size of ~300 nm, with a polydispersity index of ~0.20, zeta potential of ~ -28 mV and encapsulation efficiency of 92.31%. Thermal analysis demonstrated that the production process reduced the lipid crystallinity of the SLN matrices, which displayed a spherical morphology by scanning electron microscopy (SEM). The mathematical fitting of the release profile demonstrated that PZQ followed the Weibull model whereas PZQ-loaded SLN the Peppas model. PZQ-loaded SLN were more effective in inducing S. mansoni death than PZQ alone. The increased drug solubility did not exhibit toxicity against human fibroblast cell lines (L929). PZQ-loaded SLN demonstrated great parasiticidal properties, being an improved alternative to the classical treatment of schistosomiasis.