To detect the molecular characterization of polysaccharide purified from Amusium pleuronectes, so as to investigate its role of intervention to the formation of hepatic fibrosis caused by Schistosoma japonicum infection. The crude polysaccharide from A. pleuronectes was extracted and further purified, and the molecular weight and monosaccharide composition were determined by the high pressure size exclusion chromatography and PMP pre-column derivatization method, respectively. A total of 50 female BALB/c mice were randomly divided into five groups:A (normal group), B (experimental group), C (polysaccharide group), D (praziquantel), and E (polysaccharide + praziquantel group). The mice in B, C, D, or E groups were attacked on the abdominal skin by using the cercariae of S. japonicum (30 ± 2 for each mouse) respectively. After 8 weeks, the mice in C, D, and E groups were administrated by polysaccharide and/or praziquantel, and the mice in B group were instead of saline. All the livers and sera were collected after 16 weeks. HE staining was employed for the livers, and serum IFN-γ and IL-13 were measured by using ELISA kits. The molecular weight of purified polysaccharide from A. pleuronectes was 11.7 kDa. Compared with A and B groups, the serum levels of IFN-γ in C, D, and E groups were significantly increased (F = 63.525, P < 0.01). However, the serum levels of IL-13 in C, D, and E groups were significantly decreased (F = 99.788, P < 0.01) compared with that in B group. HE staining showed that the egg nodules and hepatic fibrosis were observed in B, C, D, and E groups. The number of egg nodules and fibrosis degree in E group were milder than those in B group (χ2 = 7.875, P < 0.05). The polysaccharide from A. pleuronectes has an obvious effect in preventing hepatic fibrosis process induced by S. japonicum infection, particularly combining with the administration of praziquantel.