<p>Vitiligo is a skin disease characterized by the loss of skin melanocytes, featuring the dual pathology of melanocyte damage due to oxidative stress and immune-mediated inflammation, which ultimately classifies it as an autoimmune condition. Sappanone A (SA), isolated from <i>Caesalpinia sappan </i>L., exhibits notable anti-oxidative stress and anti-inflammatory activity in various diseases. However, its potential effects and mechanisms in vitiligo remain uninvestigated. This study was designed to investigate the effects of SA on melanocytes and keratinocytes under oxidative stress and to evaluate its therapeutic potential in the monobenzone-induced vitiligo model. In vitro, SA protected PIG1 cells from H₂O₂-induced cytotoxicity and suppressed HMGB1 expression, nuclear export, and extracellular release. Furthermore, SA reduced HMGB1-induced overexpression of inflammatory cytokines in HaCaT cells, including <i>CXCL8</i>, <i>CXCL9</i>, <i>CXCL10</i>, <i>CXCL11</i>, and <i>TNF-α</i>. In vivo, SA administration alleviated monobenzone-induced depigmentation and CD8⁺ T-cell infiltration in C57BL/6 mice. Transcriptomic analysis, protein–protein interaction network construction, and molecular docking revealed that Wnt5a may be a potential target of SA, and SA significantly reversed monobenzone-induced <i>Wnt5a</i> expression and activation of noncanonical Wnt signaling. Overall, SA effectively attenuated the HMGB1-mediated inflammatory response in keratinocytes. Furthermore, it exerted repigmentation effects in monobenzone-induced vitiligo mice via inhibiting the Wnt5a-mediated noncanonical Wnt signaling pathway. These results suggest that SA is a promising therapeutic candidate for vitiligo.</p> Graphical abstract <p></p>