Aims: Owhadi is a popular commercial pistachio cultivar in Iran which could be an attractive source for natural bioactive compounds with health-promoting activity. Methods: The hulls subjected to fractionation and ethyl acetate fraction was a phenolic-enriched fraction (PEF). The PEF was encapsulated in nanoliposomes (PEF-NLs) as a newly developed delivery system. The phytochemical analysis of PEF-NLs confirmed the presence of phenolic and flavonoid compounds. Results: The PEF-NLs indicated the strong antioxidant activity through up-regulation of the antioxidant-related genes in the murine hepatocyte. The PEF-NLs indicated the notable anti-inflammatory activity by scavenging the nitric oxide (NO) and reducing the NO production in the murine macrophage cells. The PEF-NLs have also exhibited the anti-melanogenic activity through direct tyrosinase enzyme inhibition and by modulating melanin biosynthesis genes in B16F10 melanoma cells. Conclusion: The PEF-NLs possessed the promising potential to be used for controlling skin pigmentation disorders and as a skin-whitening agent in the cosmetic industry.