Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms that explain the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and signal transducer and activator of transcription 3 (Stat3)flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum. Liver injury, effector molecule levels and RNA transcriptome resequencing of liver were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there has obvious liver fibrosis. A sustained pathological process such as inflammation, oxidative stress, proliferation and apoptosis occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we found the activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver p-STAT3 deficiency alleviated infection-induced liver dysfunction, hepatic granuloma formation and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.