Monascus-fermented red mold rice (RMR) has excellent physiological efficacy on lipid metabolism and liver function. This study investigated the ameliorative effects of monascuspiloin (MP) from RMR on alcoholic liver injury in mice, and further clarified its mechanism of action. Results showed that MP intervention obviously ameliorated lipid metabolism and liver function in mice with over-drinking. In addition, dietary MP intervention reduced liver MDA levels and increased liver CAT, SOD, and GSH levels, thus alleviating liver oxidative stress induced by excessive drinking. 16S rRNA amplicon sequencing showed that MP intervention was beneficial to ameliorate intestinal microbiota dysbiosis by elevating the proportion of norank_f_Lachnospiraceae, Lachnoclostridium, Alistipes, Roseburia, Vagococcus, etc., but decreasing the proportion of Staphylococcus, norank_f_Desulfovibrionaceae, Lachnospiraceae_UCG-001, Helicobacter, norank_f_Muribaculaceae, unclassified_f_Ruminococcaceae, etc. Additionally, correlation network analysis indicated that the key intestinal bacterial taxa intervened by MP were closely related to some biochemical parameters of lipid metabolism, liver function, and oxidative stress. Moreover, liver metabolomics analysis revealed that dietary MP supplementation significantly regulated the levels of 75 metabolites in the liver, which were involved in the synthesis and degradation of ketone bodies, taurine, and hypotaurine metabolism, and other metabolic pathways. Furthermore, dietary MP intervention regulated gene transcription and protein expression associated with hepatic lipid metabolism and oxidative stress. In short, these findings suggest that MP mitigates alcohol-induced liver injury by regulating the intestinal microbiome and liver metabolic pathway, and thus can serve as a functional component to prevent liver disease.