The β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold confers tyrosinase inhibitory activity, and in the present study, 16 ()-5-(substituted benzylidene)-3-phenyl-2-thioxooxazolidin-4-one analogues containing this scaffold were synthesized. Mushroom tyrosinase inhibitory activities were examined. Compound (IC = 4.70 ± 0.40 μM) and compound (IC = 11.18 ± 0.54 μM) inhibited tyrosinase by 4.9 and 2.1-fold, respectively, and did so more potently than kojic acid (IC = 23.18 ± 0.11 μM). Kinetic analysis of tyrosinase inhibition revealed that and inhibited tyrosinase competitively. Results of docking simulation with mushroom tyrosinase using four docking programs suggested that and bind more strongly than kojic acid to the active site of tyrosinase and supported kinetic findings that both compounds are competitive inhibitors. The docking results of human tyrosinase homology model indicated that and can also strongly inhibit human tyrosinase. EZ-cytox assays revealed and were not cytotoxic to B16F10 melanoma cells. The effects of and on cellular tyrosinase activity and melanin production were also investigated in α-MSH- and IBMX-co-stimulated these cells. Both compounds significantly and dose-dependently reduced tyrosinase activity, and at 10 µM were more potent than kojic acid at 20 µM. Compounds and also inhibited melanogenesis, which suggested that the inhibitory effects of these compounds on melanin production were mainly attributable to their inhibitions of tyrosinase. These results indicate that compounds and with the PUSC scaffold have potential use as whitening agents for the treatment of hyperpigmentation-associated diseases.