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Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with plerixafor (1–10 nM) with or without hydroquinone, followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin pro-filing, Transwell migration assays, β-arrestin siRNA knockdown, Western blotting, sub-cellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical plerixafor (0.1–10 mM) on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration, while counteracting HQ-induced suppression of melanogenic genes. Plerixafor reduced cell-surface CXCR4 (consistent with β-arrestin–mediated recep-tor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished plerixafor-induced ERK phosphorylation and melanogenic responses, con-firming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs (5- to 8-fold en-richment, p< 0.05). In vivo, topical plerixafor restored HQ-induced depigmentation, in-creased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a bi-ased CXCR4 ligand in melanocytes, engaging a β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and repigmentation. These findings identify CXCR4 biased an-tagonism as a tractable pharmacologic strategy for therapeutic repigmentation in pig-mentary disorders.