In conclusion, our findings demonstrated that cudraflavone C induced cytotoxicity in the A375.S2 melanoma cells through mitochondrial ROS production, MAPK (p38/ERK/JNK) activation, the expression of pro-apoptotic proteins of the Bcl-2 family (Puma, Bax, Bad, Bid), and the induction of apoptosis through the mitochondrial pathway. Here, MAPK8 is linked to melanoma.