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Thirteen (<i>Z</i>)-2-(substituted benzylidene)benzimidazothiazolone analogs were synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. Among the compounds synthesized, compounds <b>1</b>–<b>3</b> showed greater inhibitory activity than kojic acid (IC₅₀ = 18.27 ± 0.89 μM); IC₅₀ = 3.70 ± 0.51 μM for <b>1</b>; IC₅₀ = 3.05 ± 0.95 μM for <b>2</b>; and IC₅₀ = 5.00 ± 0.38 μM for <b>3</b>, and found to be competitive tyrosinase inhibitors. In silico molecular docking simulations demonstrated that compounds <b>1</b>–<b>3</b> could bind to the catalytic sites of tyrosinase. Compounds <b>1</b>–<b>3</b> inhibited melanin production and cellular tyrosinase activity in a concentration-dependent manner. Notably, compound <b>2</b> dose-dependently scavenged ROS in B16F10 cells. Furthermore, compound <b>2</b> downregulated the protein kinase A (PKA)/cAMP response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways, which led to a reduction in microphthalmia-associated transcription factor (MITF) expression, and decreased tyrosinase, tyrosinase related protein 1 (TRP1), and TRP2 expression, resulting in anti-melanogenesis activity. Hence, compound <b>2</b> may serve as an anti-melanogenic agent against hyperpigmentation diseases.