Although hypoxic/ischemic injury is thought to contribute to the incidence of Alzheimer’s disease (AD), the molecular mechanism that determines the relationship between hypoxia-induced β-amyloid (Aβ) generation and development of AD is not yet known. We have now investigated the protective effects of N,4,5-trimethylthiazol-2-amine hydrochloride (KHG26702), a novel thiazole derivative, on oxygen–glucose deprivation (OGD)–reoxygenation (OGD–R)-induced Aβ production in SH-SY5Y human neuroblastoma cells. Pretreatment of these cells with KHG26702 significantly attenuated OGD–R-induced production of reactive oxygen species and elevation of levels of malondialdehyde, prostaglandin E2, interleukin 6 and glutathione, as well as superoxide dismutase activity. KHG26702 also reduced OGD–R-induced expression of the apoptotic protein caspase-3, the apoptosis regulator Bcl-2, and the autophagy protein beclin-1. Finally, KHG26702 reduced OGD–R-induced Aβ production and cleavage of amyloid precursor protein, by inhibiting secretase activity and suppressing the autophagic pathway. Although supporting data from in vivo studies are required, our results indicate that KHG26702 may prevent neuronal cell damage from OGD–R-induced toxicity.