The accumulation and neurotoxicity of amyloid β protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aβ have been still deficient up to now. According to a most recent study, (D-Ser2) Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aβ1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aβ1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aβ1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aβ1-42-induced [Ca(2+)]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3β (GSK3β) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aβ1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential.