One novel enzymatic-extractable polysaccharide (ES1) from fruiting bodies of Laetiporus sulphureus was obtained by isolation and purification using a DEAE Seplife FF chromatographic column and a Sephacryl S-400HR column. The hepatoprotective ability of ES1 against chronic alcoholic liver disease (ALD) and its underlying mechanism were explored. The results indicated that ES1 could alleviate liver damage in ALD mice by activating sequestosome-1/nuclear factor E2-related factor 2 (P62/Nrf2) pathway to increase antioxidant enzyme activities against oxidative stress, regulating adenosine monophosphate-activated protein kinase (AMPK) pathway to promote fatty acid oxidation and inhibit cholesterol synthesis against lipid metabolism disorders, and improving gut microbiota (increasing the relative abundances of Ligilactobacillus and Akkermansia, and reducing the relative abundances of Enterococcus, Romboutsia, Allobaculum, Coriobacteriaceae_UCG-002, Dubosiella and Faecalibaculum) against intestinal barrier dysfunction. Meantime, structural analysis showed that ES1 with molecular weight of 25.79 kDa was composed of α-D-Manp-(1→, →2,6)-α-D-Galp-(1→, →6)-α-D-Galp-(1→, →3)-α-L-Fucp-(1→, and α-D-Glcp-(1→, and its structure was also inferred. Therefore, these data support the application of ES1 as a potential functional food or drug for treating ALD.