This study aimed to study the effect and mechanism of action of SO2-induced oxidation on human skin keratinocytes.Different concentrations of SO2 derivatives (0, 25, 50, 100, 200, 400, and 800 μM) were used for treating HaCaT keratinocytes for 24 hours. MTT was used to evaluate the effect of each concentration on cell proliferation. HaCaT cells were randomly divided into control and SO2 groups. The control group received no treatment, whereas the SO2 group was treated with SO2 derivatives of selected concentrations for 24 hours. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD), tumor necrosis factor TNF-α (TNF-α), and interleukin-1 (IL-1-β) in cell supernatants were detected using enzyme-linked immunosorbent assay. Real-time polymerase chain reaction was used to detect the expression of nuclear transcription factor (Nrf2) and heme oxygenase (HO)-1 mRNA. The Western blot analysis was used to test the expression levels of Nrf2, HO-1, activated caspase-3, Bcl-2, Bax, IκB, NF-κB p65 (p65), ERK1/2, p38, phospho-NF-κB p65 (p-p65), p-ERK1/2, and p-p38.SO2 derivatives (100, 200, 400, and 800 μM) could inhibit cell proliferation. SO2 derivatives increased the level of ROS, MDA, TNF-α, IL-1β, Nrf2, HO-1, and p-p65/p65 and decreased the levels of SOD, IκB, p-ERK1/2/ERK1/2, and p-p38/p38 compared with the control group, but they had no effect on the levels of caspase-3, Bcl-2, and Bax.SO2 could inhibit the proliferation of human skin keratinocytes and induce oxidative stress and inflammation via the activation of the NF-κB pathway to inhibit the ERK1/2 and p38 pathways.