Objective: This study aims to investigate the mechanism of lansoprazole on skin inflammation through in vivo and in vitro experiments. Methods: In vivo experiment, mice were given continuous gavage for 6 months. The skin tissue damage of mice was evaluated and analyzed by hematoxylin-eosin staining (HE staining) and immunohistochemistry (IHC). In vitro experiment, CCK-8 was used to determine the changes of HaCaT cell viability after incubation with 10-200 μmol/L lansoprazole for 24 h and 48 h. After incubation with 10 μmol/L, 20 μmol/L and 40 μmol/L lansoprazole for 24 h and 48 h, respectively, the phosphorylation levels of NF-κB in HacaT cells and the protein expressions of interleukin 6 (IL-6) and interleukin 1β (IL-1β) in HacaT cells were detected by Western blot. In addition, the protein expressions of P-p65, IL-6 and IL-1β in HacaT cells were detected after 24 h and 48 h incubation of HacaT cells with pyrrolidine dithiocarbamate, an inhibitor of NF-κB signaling pathway, alone or in combination with lansoprazole. Results: In vivo experiments showed that lansoprazole can cause skin damage in mice. In vitro studies found that lansoprazole can decrease cell viability, increase the expression of P-p65 proteins, mediate the activation of the pathway, and further stimulate the expression of inflammatory cytokines IL-6 and IL-1β. PDTC can inhibit the lansoprazole-mediated activation of NF-κB pathway and reduce the expression of inflammatory factors. Conclusion: Lansoprazole can promote the expression of inflammatory factors and induce skin injury, and the mechanism may be related to the activation of NF-κB signaling pathway.