To investigate the effect of interleukin-22 (IL-22) on the activation and proliferation of hepatic stellate cells (HSCs) induced by acetaldehyde, as well as the role of the antioxidant axis Nrf2-keap1-ARE. Hepatic stellate cell-T6 (HSC-T6) cells were cultured in vitro, and after 24 and 48 hours of acetaldehyde stimulation at various concentrations (25, 50, 100, 200, and 400 μmol/L), MTT assay was used to measure cell proliferation rate to screen out the optimal conditions for model establishment. HSC-T6 cells were treated first with the optimal concentration of acetaldehyde (200 μmol/L) for 24 hours and then with different concentrations of IL-22 (10, 20, and 50 ng/ml) for 24 hours. MTT assay was used to measure cell proliferation, Western blot and cell immunohistochemistry were used to measure the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and α-smooth muscle actin (α-SMA), and spectrophotometry was used to measure the changes in the content of malondialdehyde (MDA) and reduced glutathione (GSH) in culture supernatant. SPSS 17.0 was used for statistical analysis and data were expressed as mean±SD. < 0.05 was considered statistically significant. A one-way analysis of variance was used for comparison of means between any two groups. HSCs had significantly enhanced proliferation and activation after being treated with acetaldehyde, especially at 200 μmol/L for 48 hours. After the intervention with gradient concentrations of IL-22, the proliferation and activation of HSCs were inhibited in a dose-dependent manner, and the proliferation and migration rates in the 10, 20, and 50 ng/ml IL-22 groups were 14%, 25%, and 35%, respectively (all < 0.05). The results of Western blot and immunohistochemistry showed that there was no significant difference in the expression of Nrf2 total protein in HSCs between groups, while there was extremely low expression of Nrf2 nucleoprotein in the blank control group. There was increased expression of Nrf2 nucleoprotein after acetaldehyde stimulation (compared with the blank control group, < 0.05), and after the intervention with gradient concentrations of IL-22, the expression of Nrf2 nucleoprotein was further increased (all < 0.05). The results of spectrophotometry showed that compared with the blank control group, the model group had increased levels of MDA and GSH in culture supernatant after acetaldehyde stimulation; after the intervention with gradient concentrations of IL-22, there was a significant reduction in the MDA level and a significant increase in the GSH level in a dose-dependent manner (all < 0.05). The activation and proliferation of HSCs induced by acetaldehyde helps with the successful establishment of an in vitro model of alcoholic liver fibrosis. IL-22 effectively inhibits the activation and proliferation of HSCs induced by acetaldehyde, and its mechanism may be related to promoting Nrf2 nuclear translocation in HSCs and expression of the downstream target gene GSH and increasing the activity of the antioxidant axis Nrf2-keap1-ARE.