Skin-lightening effects of traditional Chinese medicine (TCM) are widely recognized, yet the underlying molecular mechanisms remain unclear. In this study, we investigated ten commonly used TCM extracts for their ability to inhibit tyrosinase from mushrooms, humans, and mouse melanoma B16F0 cells. Among the extracts tested, Rosa rugosa Thumb, Morus alba L., and Paeonia lactiflora Pall displayed strong inhibitory effects on both mushroom and human tyrosinase at 1.0 mg/mL. Several other extracts, including Bletilla striata, Centella asiatica, Cynanchum atratum, Rosa canina, Rhus chinensis, and Glycyrrhiza uralensis, selectively inhibited one of the two tyrosinase sources, whereas Tribulus terrestris L. showed negligible activity. In cellular experiments using B16F0 melanoma cells, M. alba markedly decreased both tyrosinase activity (by 70%) and melanin production (by 50%) at 250 μg/mL. Overall, nine of the ten tested TCM extracts demonstrated potential as depigmenting agents. Furthermore, the variable responses observed across tyrosinase from different species highlight the importance of multi-source enzyme assays when evaluating candidates for human skin-lightening applications.