Hepatic schistosomiasis is the most well-known form of chronic disease, with a wide variety of clinical symptoms. The aim of this study was to assess the schistosomicidal effect of the aqueous methanolic extract of Opuntia ficus-indica flowers in-vivo regarding disease progression in a comparative experimental study to praziquantel (PZQ). Phytochemical investigation of flowers extract resulted in thirteen phenolic and flavonoid compounds. Structures of these compounds were elucidated by UV and 1D⁄2D 1H⁄ 13C NMR spectroscopy and compared with the literature data. From the 49th day after infection, mice infected with Schistosoma mansoni were given the extract (200 mg/kg) orally every day for 5 days, whereby the Praziquantel (500 mg/kg) was used as reference drug. The parasitological parameters (total worm burden, tissue egg load and oogram pattern) per gram of liver or intestinal tissue of the infected and the treated mice were counted. A histopathological examination of the liver granuloma took place as well. Opuntia ficus-indica extract caused a substantial decrease in the number of worms and eggs (%); the extract also decreased worm and egg burdens moderately. The results demonstrated the flower extract as a promising antischistosomal activity due to the parasitological and histopathological changes induced, besides it highlights the importance of its polyphenolic constituents.