Hyperpigmentation disorders are of social and cosmetic concerns to many individuals due to their prevalent locations on highly visible parts of the body. Topical formulation containing hydroquinone is the most widely used remedy for the treatment of hyperpigmentation disorders. However, reports of side effects in long-term usage have raised concerns for its use in cosmetic products. Thus, it is highly desirable to develop a safe and effective alternative to treat hyperpigmentation disorders. The objective of the current study is to investigate the de-pigmenting efficacy of 4-hexyl-1,3-phenylenediol in various in vitro models and in a randomized controlled clinical study. We showed that 4-hexyl-1,3-phenylenediol significantly reduced melanogenesis in primary human melanocytes, murine melanoma cells, and pigmented human epidermal equivalents. It was determined that the reduction in melanogenesis is mediated through inhibition of tyrosinase enzyme activity and protein expression. Further investigation revealed that the inhibition of melanogenesis is reversible and is not associated with cellular toxicity in melanocytes. In addition, significant improvements in key clinical parameters such as overall skin lightening, appearance of spots on the cheeks, overall contrast between spots and surrounding skin, and overall pigmentation size were detected in a double-blinded, randomized controlled clinical study. In conclusion, our findings clearly demonstrated the potency of 4-hexyl-1,3-phenylenediol in modulating skin pigmentation, and it is safe and well tolerated after 12-week topical application.