Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and there is a need to identify new targets for chemotherapeutic interventions. Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9 has not been investigated in detail, so far. We demonstrated that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. SmPOP was produced in the bacterial expression system and its active site specificity was investigated using synthetic substrate libraries and a SmPOP homology model. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline-containing hormones such as angiotensin and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that are effective against schistosomes. Our results suggest that SmPOP plays a role in host-parasite interactions and is a potential target for the development of anti-schistosomal drugs.