Many bioactivities of hydrolysates from oyster (Crassostrea gigas) muscle have been reported, while there is no knowledge about their protective effects on alcohol-induced liver disease (ALD). In the present study, the anti-oxidative activities in vitro and molecular weight distribution of oyster protein hydrolysates (OPH) were detected and the OPH released by alcalase (AOPH) was used to treat C57BL/6 mice. C57BL/6 mice were treated with a Lindros control diet to establish an ethanol-exposed model. The content of small-weight components (<2.0 kDa) of OPH reached 90.85%. AOPH showed more potent antioxidant activities in vitro with higher reducing power and ferric reducing antioxidant power (FRAP), and those capacities could be maintained at a high level after simulated gastrointestinal digestion. Compared to the model mice, oral administration (4 weeks) of AOPH at 800 mg per kg body weight could lead to a decline in T-AOC, GSH-PX, and ADH in the liver. The hepatocellular lesions were effectively relieved and impaired liver tissue development was successfully inhibited. A total of 834 genes and 54 proteins showed differential expression in the AOPH group and the oxidative metabolic pathways of ethanol such as oxidative phosphorylation, glutathione metabolism, peroxisomes, the PPAR signaling pathway and drug metabolism-cytochrome P450 play a preeminent role in ALD according to the results of transcriptomics and proteomics. The beneficial effects of AOPH were available in the improvement of ALD. These results revealed that AOPH intervention ameliorated ALD by affecting oxidative metabolism and highlighting AOPH's potential application as a functional food.