The emerging data show that the insulinotrophic hormone glucagon-like peptide-1(GLP-1) and its agonist extendin-4 have neurotrophic function to inducing neuronal differentiation of PC12 cells and prevent neurons damage challenged by oxidative stress. Here, with the model of high throughput screen for GLP-1 receptor agonists, we screen and identify that geniposide is a novel agonist for GLP-1 receptor. Furthermore, geniposide induces the neuronal differentiation of PC12 cells with resulting neurites outgrowth; we also observe an increase in expression of growth-associated protein-43. U0126, a selective MEK inhibitor, prevents neurites out growth and phosphorylation of mitogen-activated kinase proteins in PC12 cells induced by geniposide. All these results show that activation of GLP-1 receptor by geniposide to induce the neuronal differentiation of PC12 cells involves in MAPK signaling cascade.