Abstract: Objective: To investigate the protective effect and mechanism of abalone visceral polysaccharide-protein complex selenium nanoparticles (Abalone Visceral Polysaccharide-protein Complex Selenium Nanoparticles, PSP-SeNPs) on alcohol-induced damage in AML12 cells. Methods: After pretreated with different levels of PSP-SeNPs (0.1, 0.2, 0.3, and 0.4 µg/mL) for 24 h, AML12 cells were further treated with 300 mmol/L alcohol for 24 h to establish cell injury model. Hoechst staining was used to assess the degree of cell injury, and biochemical indicators related to oxidative stress were measured. Finally, qRT-PCR was used to measure the expression of oxidative stress-related genes in AML-12 cells. Results: Compared with the normal control group, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) in the alcohol model group were significantly decreased (P<0.05), while the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were significantly increased (P<0.05). These changes were significantly reversed by PSP-SeNPs (P<0.05). qRT-PCR results showed that the mRNA levels of nuclear factor E2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), catalase (CAT), and glutamate-cysteine ligase regulatory subunit (GCLM) were significantly decreased in the alcohol model group as compared with the control group (P<0.05). Additionally, the alcohol induced up-regulation of Kelch-like ECH-associated protein 1 (Keap1) mRNA was significantly reversed by PSP-SeNPs (P<0.05). Conclusion: PSP-SeNPs can alleviate alcohol-induced AML12 cell injury by regulating the expression levels of oxidative stress-related genes and modulating the activities of antioxidant enzymes.