Psoriasis vulgaris (PV) is a common inflammatory skin disorder with immune imbalance contributing to its pathology. It has been reported that auranofin, a known anti-rheumatic drug, has the therapeutic effects on inflammatory diseases. However, the effects and underlying mechanisms of auranofin on PV have not been reported. Here, we showed that auranofin significantly attenuated the mixture of five proinflammatory cytokines (termed as M5) induced hyperproliferation and inflammation in HaCaT cells, a kind of human immortalized keratinocyte cell line. Topical administration of auranofin markedly alleviated the imiquimod (IMQ)-induced mouse psoriatic dermatitis both in appearance and in pathology. The psoriasis area and severity index (PASI) score, acanthosis, dermal infiltrated inflammatory cells and Ki-67 expression were improved obviously. The results of RNA-sequencing from both M5-induced HaCaT cells and IMQ-treated mouse dermatitis showed that auranofin could regulate inflammation-related signaling pathway. Meanwhile, we observed that fatty acid 2-hydroxylase (FA2H), a key molecule in lipid metabolism, was significantly increased after auraonfin treatment in both M5-induced HaCaT cells and IMQ-treated mouse skin. Knockdown of FA2H in HaCaT cells remarkably inhibited cell apoptosis, increased cell proliferation and the expression profiles of inflammatory-related genes, whereas FA2H overexpression had opposite effect. In conclusion, auranofin notably alleviated IMQ-induced psoriasis-like skin inflammation, which might be mediated by increasing FA2H expression, suggesting its potential to be a novel strategy for psoriasis treatment.