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The Wnt/β-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/β-catenin pathway involved in hair re-growth and wound-induced hair follicle neogenesis (WIHN) via an interaction with Dishevelled (Dvl). CXXC5 was up-regulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5-/- mice displayed accelerated hair re-growth and treatment with valproic acid, a glycogen synthase kinase 3β inhibitor that activates the Wnt/β-catenin pathway, further induced hair re-growth in the CXXC5-/- mice. Disrupting the CXXC5-Dvl interaction with a competitor peptide activated the Wnt/β-catenin pathway and accelerated hair re-growth and WIHN. Overall, these findings suggest that the CXXC5-Dvl interaction is a potential target for treatment of hair loss.