Concanavalin A (Con A), a mannose/glucose-binding legume lectin, can induce cancer cell death through a mitochondria-mediated autophagic pathway; however, the precise mechanisms by which it mediates cell death are still only rudimentarily understood. In the present study, Con A possesses a remarkable antiproliferative effect on human melanoma A375 cells. Also, there is a link between the antiproliferative activity of Con A and its sugar-binding activity. Subsequently, Con A can induce human melanoma A375 cell apoptosis in a caspase-dependent manner. In addition, the treatment with Con A can cause mitochondrial transmembrane potential collapse, leading to cytochrome c release and caspase-9-caspase-3 activation. In conclusion, we demonstrate that there may be a close correlation between the antiproliferative activity of Con A and its sugar-binding activity. More importantly, we report for the first time that Con A can induce human melanoma A375 cell death in a caspase-dependent manner as well as via a mitochondrial apoptotic pathway.