Abstract. The present study aimed to investigate the effect of goniothalamin on apoptosis induction in the A375 melanoma cell line. Melanoma is a type of skin cancer with increased prevalence and no potential standard treatment. Goniothalamin is a plant, bioactive styrly-lactone, which has various bioactivities including anti-microbial, anti-inflammatory and anti-cancer. Apoptosis induction by goniothalamin has been studied in numerous cancer cell lines, however not in the melanoma cell line A375. The results of the MTT assay demonstrated that goniothalamin induced anti-proliferation in a dose dependent manner. Hoechst staining assay demonstrated that goniothalamin induced chromatin condensation and apoptotic bodies in A375 treated cells, and JC-1 staining revealed that goniothalamin induced mitochondrial membrane dysfunction in A375 cells. In addition, goniothalamin decreased the level of anti-apoptotic proteins myeloid cell leukemia 1, B cell lymphoma (Bcl)-2 and Bcl-extra large, whereas it increased the level of pro-apoptotic proteins, Bcl-2 Associated X, apoptosis regulator, t-BID and Bim in A375 treated cells. In addition, goniothalamin also increased active caspase-9, -7 and cleaved-poly (ADP-ribose) polymerase expression in A375 treated cells. Furthermore, phosphorylated (p)-pyruvate dehydrogenase kinase (PDK) 1 (Ser241) and p-RAC-alpha serine/threonine-protein kinase (Akt; Ser473) were decreased, however c-Jun and p-extracellular signal-regulated kinase (ERK)1/2 were increased upon goniothalamin treatment. These results suggest that goniothalamin has an effect, as anti-proliferation and apoptosis induction in A375 cells were associated with upregulated p-ERK1/2, c-Jun and downregulated p-PDK1 (Ser241), p-Akt (Ser473) in A375 cells. Therefore, goniothalamin may be a potential candidate for anti-cancer drug development for melanoma treatment.