Background and Purpose: Vitiligo, a common depigmenting skin disorder, is characterised by the selective loss of melanocytes, which leads to distinctive non-scaly, chalky-white macules. Galangin (GA), a flavonoid found in galangal and propolis, our previous study highlighted the therapeutic potential of GA. However, the contributions of GA to restoring skin pigmentation and maintaining immune homeostasis, as well as its detailed molecular roles in vitiligo management, have not been fully elucidated. Experimental Approach: We used H2O2-induced vitiligo mice and imiquimod-induced erythema mice to test the anti-vitiligo effects and anti-inflammatory effects of GA. We also revealed the potential mechanism by immunoprecipitation-mass spectrometry, pull-down assays, Autodock and surface plasmon resonance analysis in cells. Key Results: We found that GA exerts anti-inflammatory and antioxidant effects through a dual mechanism: it promotes melanocyte proliferation while inhibiting macrophage proliferation. Using immunoprecipitation-mass spectrometry, pull-down assays, Autodock and surface plasmon resonance analyses, we revealed that GA binds to Annexin A2 (ANXA2) and promotes its degradation in macrophages. This interaction led to the inhibition of macrophage proliferation and activation. In vivo, GA administration significantly improved skin conditions in H2O2-induced vitiligo mice and imiquimod-induced erythema mice. Furthermore, ANXA2 knockout abolished the protective effects of GA in these models. Conclusion and Implications: Our findings provide novel evidence of GA’s dual mechanism in vitiligo treatment, which involves selective binding and degradation of ANXA2 in macrophages. These results support the potential clinical application of GA for vitiligo therapy.