Anti-IL-17A antibodies, such as secukinumab and ixekizumab, are effective proinflammatory cytokine inhibitors for autoimmune disorders, including psoriasis. However, anti-IL-17A small molecule treatments are yet to be commercialized. Celastrol, a natural compound extracted from the roots of traditional Chinese medicinal plants, has anti-inflammatory and antioxidant properties. However, the binding of celastrol to IL-17A and the associated anti-inflammatory mechanisms remain unclear. This study investigated whether celastrol could directly bind to IL-17A and regulate inflammation in psoriatic in vitro and in vivo models. The results showed that celastrol directly binds to IL-17A and inhibits its downstream signaling, including the NF-kB and MAPK pathways. Interestingly, celastrol restored autophagy dysfunction and reduced proinflammatory cytokine secretion in keratinocytes. In addition, celastrol increased autophagy in the epidermis of a mouse model of psoriasis. Celastrol decreased Th17 cell populations and proinflammatory cytokine levels in mice. Thus, IL-17A-targeting celastrol reduced inflammation by rescuing impaired autophagy in in vitro and in vivo models of psoriasis, demonstrating its potential as a substitute for anti-IL-17A antibodies for treating psoriasis.