Schistosomiasis affects millions globally. There is no vaccine, and treatment depends entirely on praziquantel (PZQ). Field isolates exhibit reduced susceptibility to PZQ, and resistance has been experimentally induced, suggesting that reliance on a single treatment is particularly dangerous. The present study investigated the value of cinnarizine and griseofulvin against Schistosoma mansoni through their in vitro effects on adult worms and oviposition as well as in vivo evaluation in early and late infection, compared to PZQ, in a preliminary experimental model. In vitro, both cinnarizine and griseofulvin showed uncoupling, sluggish worm movement and complete absence of ova at 100 μg/ml. In early infection, cinnarizine showed a significant reduction in the number of porto-mesenteric couples compared to the griseofulvin and control groups, a finding similar to PZQ. Remarkably, cinnarizine significantly exceeded PZQ and griseofulvin in reducing the total worm burden. In late infection, cinnarizine and griseofulvin showed results similar to PZQ by significantly reducing the numbers of hepatic and porto-mesenteric couples and total worm burden compared to controls. Cinnarizine performed better than griseofulvin by reducing hepatic and intestinal ovum counts, and it led to complete disappearance of the first two immature stages. The current work suggests the possibility of using cinnarizine and griseofulvin, mainly in late S. mansoni infection, especially cinnarizine, which showed similar results to PZQ and surpassed it in early infection. Further studies are required to elucidate their exact mechanisms of action and particularly their synergistic effect with PZQ.