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&NA; This study aimed to investigate whether mangiferin played a protective role in a well‐established dermatitis mouse model and tumor necrosis factor alpha (TNF‐&agr;)‐induced RAW264.7 macrophages. Contact dermatitis is an inflammatory skin disease in the clinic, while its underlying mechanism still remains to be elucidated. Mangiferin, 1,3,6,7‐tetrahydroxyxanthone‐C2‐&bgr;‐D‐glucoside (C‐glucosyl xanthone), a natural antioxidant that was reported to inhibit inflammatory reactions, has been recently proved to be a potential therapy for inflammation. As a result, the oxazolone‐induced dermatitis mice models were established to explore whether mangiferin has an anti‐inflammatory role in vivo. The phosphate‐buffered saline treatment groups showed emblematic skin inflammation, whereas the administration of mangiferin obviously inhibited dermatitis in the mice models. Furthermore, exogenous mangiferin alleviated the inflammatory reaction in TNF‐&agr;‐induced macrophages by suppressing the production of inflammation‐ and oxidative stress–associated molecules. Also, mangiferin treatment repressed the activation of nuclear factor‐kappaB signaling pathway. To sum up, mangiferin could provide a new target for the therapy and prevention of skin inflammation. HighlightsMangiferin could provide a new target for prevention of skin inflammation.Mangiferin repressed activation of NF‐&kgr;B signaling pathway in vivo.Mangiferin played a positive role in inhibiting dermatitis.Mangiferin may serve as a potential therapeutic agent against skin inflammation.