Apoptosis is the main form of β-cell death in diabetes. Ginseng has been used as an anti-diabetic herb for several thousand years in Asia with ginsenoside Rg1 and ginsenoside Rb1 as important active ingredients. In this study, we demonstrated ginsenoside Rg1 and Rb1 protect β-cells from high glucose/cytokine-induced pancreatic β-cell apoptosis via inhibiting nitric oxide (NO) production and regulating apoptosis-related genes. Among these genes, Bax, Fas and Caspase-3 gene expressions were up-regulated by high glucose, whereas only Bax and Caspase-3 gene expression were elevated by cytokines. In these two stimuli-induced apoptotic cells, Rg1 down-regulated Fas gene expression, while Rb1 decreased Caspase-3 gene expression. As a conclusion, Fas signal pathway and mitochondria stress is mostly related to anti-diabetes function of ginsenoside Rg1, while Caspase-3 pathway is essential when Rb1 is present.