Prolonged and unprotected exposure to the environment explicitly influences the development of hyperpigmented lesions. The enzyme tyrosinase (TYR) is a key target for regulating melanin synthesis. Several bioactive compounds derived from plant extracts have been found to possess potent anti-melanogenesis properties against TYR. In particular, the potential of banana peels from various varieties has garnered interest due to their application in skin hyperpigmentation treatment. A molecular docking study demonstrated interactions between rosmarinic acid, which is predominantly found in all Hom Thong peel extracts, and the active site of TYR (PDB ID: 2Y9X) at residues HIS263, VAL283, SER282, and MET280, with the lowest binding energy of −5.05 kcal/mol, showing the strongest interaction. Additionally, Hom Thong banana peels are rich in phenolic compounds that could inhibit melanin content and tyrosinase activity in both human and mouse melanoma cells. These effects may be attributed to the suppression of gene expression related to melanogenesis, including the regulator gene MITF and pigmentary genes TYR, TRP-1, and DCT, indicating effects comparable to those of the standard treatment groups with arbutin and kojic acid. Our findings indicated the potential of Hom Thong peel extracts as anti-melanogenic agents.