Hepatic fibrosis resulting from human mansonic schistosomiasis significantly impairs liver function and contributes substantially to morbidity associated with helminth infections. This pathological state develops following the deposition of helminth eggs within hepatic tissues, triggering a granulomatous inflammatory reaction. Schistosomiasis, a neglected tropical disease affecting approximately 240 million individuals globally, represents a major public health challenge. Although praziquantel (PZQ) is recommended by the World Health Organization (WHO) as the primary treatment for helminth infections, additional therapies are required to address the associated liver fibrosis. This study investigated the efficacy of tetramethylpyrazine (TMP), a natural compound known for its anti-inflammatory, antifibrotic, and hepatoprotective properties in various experimental models, in mitigating hepatic fibrosis induced by mansonic schistosomiasis. Our in vivo experiments demonstrated that TMP treatment significantly reduced hepatic granuloma size, as evidenced by histological analysis. Furthermore, our in vitro studies showed that TMP increased levels of the anti-inflammatory cytokine IL-10 while decreasing levels of the profibrotic cytokine IL-13 in a concentration-dependent manner. Immunofluorescence analysis also revealed that TMP effectively inhibited collagen deposition. Collectively, these findings suggest that TMP exhibits potential as an anti-inflammatory and antifibrotic agent for hepatic fibrosis resulting from Schistosoma mansoni infection.