Aloe vera (L.) Burm. f. is well known for its beneficial effects on the skin. Moreover, the antioxidant, immunostimulant, and anticancer effects of the plant leaf extracts have been reported in scientific research. This study was conducted to demonstrate the cytotoxic effects of several leaf extracts and aloe emodin (AE) on a type of skin cancer. A. vera aqueous and methanolic extracts of fresh leaves, methanolic extract of dried leaves, and leaf gel extract (AVG) were prepared separately. Cytotoxicity was assessed using the MTT test. Apoptosis and necrosis were detected by flow cytometry using Annexin V/PI. All the extracts exhibited a selective cytotoxic effect on the cells. The mechanism of AVG cytotoxicity on B16F10 murine melanoma cells was found to be apoptosis, whereas that of AE was necrosis. The observation that treatment with AVG delayed the apoptosis in NIH3T3 cells, while it exerted an apoptotic activity on B16F10 cells, provides some scientific evidence for the folkloric and alternative uses of A. vera gel as a protective and skin healer. Therefore, A. vera gel and aloe emodin can be used as potential targets for anticancer drug research.