Schistosomiasis is a prevalent epidemic disease in Egypt. As a result of the exclusive use of praziquantel (PZQ) in the treatment of schistosomiasis, the parasite may become resistant to the medication. Accordingly, there has been a growing interest in research with the aim of developing novel antischistosomal medicines from natural sources. The marine Hyrtios sponge exhibits bioactive compounds, qualifying it to explore novel drugs. Hence, the current study aimed to assess the in vitro activity of the Hyrtios sponge extract (HSE) against schistosomiasis through the detection of mortality and tegumental alterations in S. mansoni adult worms.  The mortality rates of S. mansoni worms exceeded 50% after 2 and 3 hours of exposure to a concentration of 200µg/ ml of HSE. After 24 hours, mortality rates surpassed 50% at concentrations of both 100 and 200µg/ ml. Additionally, after 36 and 48 hours, mortality rates reached above 50% across concentrations ranging from 60 to 200µg/ ml. Furthermore, after 48h, the mortality rate of S. mansoni worms reached 100% at a 200µg/ ml concentration. After exposing the S. mansoni worms to HSE for 24h, the lethal concentration values (LC₅₀ and LC₉₀) were 115.40 and 241.19µg/ ml, respectively. These lethal concentrations became 59.36 for LC₅₀ and 144.11µg/ ml for LC₉₀ after 48h of exposure. Scanning electron microscopy revealed morphological changes in both male and female worms at concentrations of 100 and 200μg/ ml following a 48-h in vitro treatment of S. mansoni worms with the HSE compared to the control group. Morphological abnormalities in male worms included swollen or flattened bodies, self-coiling contractions, tegument shrinkage, invaginations, erosion, deformed gynechophoric canal, distorted suckers, and smooth tubercles with blebs between them. The female body displayed morphological alterations, including swollen body, shrinkage of the ventral sucker, a pitted tegument with corrugation, folds, invaginations, wrinkles, erosions, and blebs in addition to the absence of body spines. The death of S. mansoni worms caused by HSE exposure could be associated with its effect on their tegumental surface and may be related to the existence of different antioxidant phytochemicals like alkaloids, saponins, phenolics, and flavonoids in this extract. In conclusion, HSE has an effective antischistosomal impact and can be considered an adjuvant medication for PZQ in S. mansoni infection.