Background: It is a consensus that selenomethionine (SeMet) can protect liver from damage, but the immune mechanism of SeMet in acute liver injury (ALI) is still unclear. This study aims to investigate the protective effects of SeMet against ALI and to elucidate the possible immune mechanism. Methods: Firstly, the role of SeMet in CCl₄-induced ALI mice was investigated through survival rate, serum ALT and AST, liver necrosis and apoptosis analysis. The expression and secretion of inflammatory cytokines and chemokines in the liver and serum of CCl₄-induced ALI mice were analyzed by qRT-PCR and ELISA. Then the immune cell phenotypes were analyzed by flow cytometry and confocal imaging. In addition, MDSCs depletion, CXCL12/CXCR4 axis blocking and selenoprotein S (SELENOS) knockdown assays were used to reveal the immune mechanism of SeMet. Results: We found that SeMet prolonged survival rate, decreased the serum ALT and AST, alleviated liver necrosis and inhibited hepatocytes apoptosis. Prospective, SeMet decreased the expression of IL-6 and TNF-α, and increased the expression of IL-10. Interestingly, SeMet decreased the expression of MCP-1, while increased the expression of CXCL12. The immune analysis showed that SeMet decreased the activation of T cells through promoting MDSCs accumulation mediated by CXCL12/CXCR4 axis. Furthermore, SeMet increased SELENOS expression in vivo, and knockdown of SELENOS effectively abolished the protective effect of SeMet during ALI. Conclusion: This study demonstrates that SeMet alleviates CCl4-induced ALI by promoting MDSCs accumulation through SELENOS mediated CXCL12/CXCR4 axis. Therefore, our study infers that selenium intake may be as a new therapeutic option for management of inflammation-mediated liver injury.