Purpose: To study the role of yes-associated protein (YAP) inhibition by verteporfin (VTF) in LPSinduced acute liver injury (ALI) after sepsis. Methods: In vitro, VTF was used to treat LPS-stimulated RAW 267.4 cells. In vivo, LPS was injected to induce sepsis in mice, followed by treatment with VTF. The inflammatory mediators were determined using quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence spectroscopy (IF) and immunohistochemical staining (IHC), and the levels of YAP, P53 and ERK were measured by qRT-PCR, WB and IHC. Moreover, liver histology and liver function were examined using HE staining and ELISA respectively. Results: The results showed that VTF reduced YAP expression and inhibited LPS-induced cell activation and inflammatory cytokine production such as IL-6 and IL-11i, by attenuating the expressions of p53 and ERK pathway in macrophages. The levels of AST, AIL and TBiL remarkably decreased in ALI mice after VTF treatment (p < 0.05). Moreover, it was observed that inflammatory mediators, including inducible nitric oxide synthase (iNOS), IL-6 and IL-11i, decreased significantly in VTF treated mice (P < 0.05). Conclusion: VTF plays an antagonistic role in LPS-induced inflammatory response after ALI. Therefore, VTF is a potential medicinal agent for preventing infectious acute liver injury.