We previously demonstrated that α-mangostin, γ-mangostin, and 8-deoxygartanin have significant cytotoxic effects on human melanoma SK-MEL-28 cell line. The current study revealed the underlying mechanisms. α-Mangostin (7.5 g/mL) activated caspase activity, with a 3-fold and 4-fold increased caspase 8 and 9 activity, respectively. The molecular mechanisms were investigated by qRT-PCR for mRNA related to cell cycle arrest in G1 phase (p21WAF1 and cyclin D1), apoptosis (cytochrome C, Bcl-2, and Bax), and survival pathways (Akt1, NFB, and IBα). α-Mangostin significantly upregulated mRNA expression of cytochrome C and p21WAF1 and downregulated that of cyclin D1, Akt1, and NFB. γ-Mangostin significantly downregulated mRNA expression of Akt1 and NFB and upregulated p21WAF1 and IBα. 8-Deoxygartanin significantly upregulated the mRNA expression of p21WAF1 and downregulated that of cyclin D1 and NFB. The three xanthones significantly inhibited the mRNA expression of the BRAF V600E mutation. Moreover, α-mangostin and γ-mangostin significantly downregulated Akt phosphorylation at Ser473. In conclusion, the three xanthones induced an inhibitory effect on SK-MEL-28 cells by modulating the molecular targets involved in the apoptotic pathways.