Background and Purpose Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by cytotoxicity of mutant huntingtin protein (mHTT). Decrease of mHTT will be a potential strategy for therapeutic purpose of HD. VCP has been reported and functioned in HD. Finding of novel small molecules specifically regulates the activity of VCP, which may be benefited to HD patients. Experimental Approach In-house screening drug library against VCP enzymatic activity was performed and a leading candidate was studied for its mechanism of the degradation of mHTT and its effect on HD animal models. Key Results We identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. Gossypol interfered with VCP’s enzymatic activity through its direct binding to interface between VCP’s N and D1 domains. Gossypol acetate not only lowered mHTT levels and rescued HD-relevant phenotypes in patient induced pluripotent stem cell (iPS)-derived neurons and HD knockin mouse striatal cell, but also improved motor function deficits in both Drosophila and mouse HD models. Conclusions and Implications Taken together, these findings revealed a new strategy for treating HD by gossypol that targets mHTT through VCP and LC3 to the autophagic pathway and raised the possibility that an existing drug can be repurposed as a new treatment of HD.