Cyclic AMP response element-binding protein (CREB) plays important roles in neuronal plasticity and amyloid β-peptide (Aβ)-induced cognitive impairment in Alzheimer's disease (AD). Here we demonstrated that Ginkgo biloba extract, EGb 761, displayed the neuron protective effect by activating the CREB signaling pathway. Wild-type neuroblastoma cells cultured in a conditioned medium containing cell-secreted Αβ exhibited reduced levels of phosphorylated CREB (pCREB). Addition of EGb 761 (100 µg/mL) or an anti-oligomer-specific antibody (A-11) to the conditioned medium could restore pCREB level. In a neuroblastoma cell line expressing Αβ, treatment with EGb 761 increased levels of pCREB and brain-derived neurotrophic factor. Furthermore, CREB phosphorylation induced by EGb 761 was blocked by inhibitors of several upstream signaling pathways of CREB, including protein kinase C, ERK, ribosomal S6 kinase(RSK)90 and nitric oxide pathway. Moreover, these inhibitors differentially blocked the effects of individual components of EGb 761, ginkgolide C, quercetin and bilobalide, which suggest diverse effects of the EGb 761 individual components. Actions of individual EGb 761 components provide further insights into direct mechanisms underlying the effect of EGb 761 on enhancing the cognitive performance of patients with AD.