Here, the aim was to evaluate the protective effect of Lactobacillus plantarum-derived postbiotics, i.e., LP-cs, on acute alcoholic liver injury (ALI). After preincubation with LP-cs, HL7702 human hepatocytes were treated with alcohol, and then the cell survival rate was measured. C57BL/6 male mice were presupplemented with or without LP-cs and LP-cs-loaded calcium alginate hydrogel (LP-cs-Gel) for 3 weeks and given 50% alcohol gavage to establish the mouse model of ALI, LP-cs presupplementation, and LP-cs-Gel presupplementation. The histomorphology of the liver and intestines; the levels of serum AST, ALT, lipid, and SOD activity; liver transcriptomics; and the metagenome of intestinal microbiota were detected in all mouse models. In vitro, LP-cs significantly increased the survival rate of alcohol-treated cells. In vivo, presupplementation with LP-cs and LP-cs-Gel restored the levels of serum AST, ALT, and SOD activity, as well as TC and TG, after acute alcohol intake. In the LP-cs-presupplemented mice, the genes involved in fatty acid metabolic processes were upregulated and the genes involved in steroid biosynthesis were downregulated significantly as compared with the ALI mice. LP-cs significantly increased the abundance of intestinal microbiota, especially Akkermansia muciniphila. In conclusion, LP-cs ameliorates ALI by protecting hepatocytes against oxidative damage, thereby, improving lipid metabolism and regulating the intestinal microbiota. The effect of LP-cs-Gel is similar to that of LP-cs.