Melanoma is the most aggressive type of skin cancer and originates from pigment-containing cells called melanocytes. The incidence of melanoma has been increasing worldwide. In the current study, the cytotoxic and photo-cytotoxic activities of different medicinal plants from Lamiaceae (Salvia cedronella,Salvia chionantha, andSalvia adenophylla), Asteraceae (Klasea kurdica,Klasea bornmuelleri, andAchillea millefolium), Apiaceae (Cuminum cyminum,andAnethum graveolens), and Polygonaceae (Rumex crispus) families were studied against HT 144 (Human malignant melanoma) cancer cell lines. The activities were performed by employing the MTT assay. Moreover, the apoptotic effects of the plant extracts were investigated by flow cytometry with annexin V/PI dual staining technique. The production of intracellular ROS by DCFH-DA technique and the effects of TNF-alpha secretion on apoptosis were also investigated. All plant extracts exhibited cytotoxic, and photo-cytotoxic effects against HT 144 cancer cells.Salviaspecies andKlaseaspecies induced apoptosis via intracellular ROS generation secreted by TNF-alpha.On the other hand,A. millefolium,C. cyminum,A. graveolens, andR. crispusextracts induced apoptosis due to the intracellular generation of ROS, but, via the different pathway. In conclusion, this study indicates that the tested medicinal plant extracts have the potential in the treatment of melanoma.