On the basis of a hit from random screening, biaryl amide derivatives were prepared in a combinatorial manner via parallel solution-phase synthesis, and their effects on melanocytes were investigated to discover new effective skin depigmenting agents. Among the 120 derivatives prepared, five members exhibited a >30% reduction of melanin production at 30 microM with a cell viability of >90%. In particular, compound A(3)/B(5) exhibited effective inhibitory activity on melanin synthesis. Although the inhibition percentage of A(3)/B(5) was slightly lower than that of the positive reference compound, phenylthiourea (PTU), A(3)/B(5) demonstrated a much better cell viability than PTU. In vivo evaluation of A(3)/B(5) also showed a significant decrease of melanin pigments. In addition, the in silico classification model was built based on the experimental data of library members. Our results suggest that these biaryl amide derivatives may act as potent skin depigmenting agents.