Schistosomiasis causes severe health problems in endemic areas of Africa, Southeast Asia, and Central and South America. Praziquantel is the drug of choice for treatment of at-risk populations; however, evolution of resistant worms under repeated treatment is of great concern. Combining praziquantel with another drug could not only increase efficacy of praziquantel, but also eventually hamper development of drug resistance. Our study reports the global praziquantel-induced transcriptional changes of Schistosoma mansoni adult worms in vitro, in the context of the mature female mating status (paired or unpaired). We identified sets of genes that were differentially affected in paired or unpaired mature females; we also identified genes that were similarly affected in males and females. Aiming to find possible new candidates to be tested as synergistic drugs, we used functional analysis of gene interaction networks to identify parasite genes whose expression was affected by praziquantel, and encode proteins whose human homologs are targets of different drugs already used to treat other diseases. This analysis suggested omeprazole, a widely prescribed drug, as a potential partner for praziquantel in a combination treatment. Finally, we demonstrated that this praziquantel-omeprazole combination resulted in increased worm lethality in vitro when compared with praziquantel or omeprazole alone.