Background <p>Schistosomiasis, an infectious disease of poverty, remains a public health challenge worldwide. Although praziquantel chemotherapy has been proven to be an effective antiparasitic intervention, real-world evidence indicates that in patients with hepatointestinal schistosomiasis, hepatic fibrosis may continue to progress even after treatment. The current understanding of the mechanisms underlying persistent liver fibrosis progression in <i>Schistosoma</i>-infected individuals post-treatment is unclear. The aim of this commentary is to analyze the critical yet multifactorial determinants contributing to the persistent progression of liver fibrosis and to advocate for a comprehensive research focus to support the global elimination of this disease.</p> Main text <p>Multiple mechanisms may contribute to the persistent progression of liver fibrosis in schistosomiasis. These include the continued presence of viable <i>Schistosoma</i> eggs, co-infection with hepatitis viruses, alterations in splenic structure and function, disruption of the intestinal mucosal barrier, hepatic ischemia and hypoxia, hepatocyte death, specific types of collagen deposition, and host genetic variations. However, additional factors potentially contributing to host pathology warrant further investigation.</p> Conclusions <p>In the post-schistosomiasis control era, expanding the focus of research to include the “post-treatment” phase is essential. Investigating the mechanisms underlying the persistent progression of liver fibrosis and identifying future research priorities may enhance efforts toward the global elimination of schistosomiasis and improve long-term health outcomes for individuals who have received praziquantel treatment.</p> Graphical Abstract <p></p>