Background and Purpose: Humans have been fighting vitiligo for centuries but still being inferior due to the lack of efficiency drugs and therapies. While some research has implied the therapeutic potential of Wnt/β-catenin signalling on curing vitiligo but correlation mechanism is not clear and no Wnt-specific anti-vitiligo drug has been reported. Here, We identified how vitiligo could be treated by regulating Wnt and two lead compounds of new anti-vitiligo drugs have been found. Experimental Approach: Wnt agonists were rational synthesized and then be evaluated their effects on vitiligo in B16 cells and C57B/L mouse. Furthermore, Co-IP and Site-directed mutagenesis were employed to indicate the mechanism and the target of the compounds. Key Results: HCJA121 and HCJA404 could significantly promote the synthesis of melanin, restore the pigmented function of skin, and improve the symptoms of vitiligo. Mechanism studies indicated that HCJA121 and HCJA404 target the DAX domain of Axin by binding to LYS781 and LEU784 then potentiate the Axin-LRP6 association and eventually promoted melanogenesis. Conclusions and Implications: These findings imply an alternative regulatory mechanism of melanogenesis and the Axin protein could be a new target for anti-vitiligo agents which reveal a therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may represent potential compounds for vitiligo treatment.