One hallmark of Alzheimer's disease (AD) is amyloid-beta (Aβ) deposition, which can initiate a cascade of oxidative events that may result in neuronal death. The present study aimed to investigate the protective effects of gastrodin, a phenolic compound which shows antioxidant activity, on Aβ(1-42)-induced neurotoxicity and the underlying mechanism for this neuroprotection. Results indicate that Aβ(1-42)-induced neuronal toxicity as measured by cell viability, which was correlated with decreased catalase (CAT) content and superoxide dismutase (SOD) activity. Pre-treatment of primary hippocampal neurons with gastrodin significantly attenuated Aβ(1-42)-induced neurotoxicity and changes in SOD and CAT, and upregulated gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation. Pharmacological blockade of ERK1/2 abrogation this action of gastrodin. The ERK1/2 pathway may be involved in the neuroprotective effect of gastrodin against Aβ(1-42)-induced oxidative in primary cultured rat hippocampal neurons. These findings suggest that gastrodin could be of importance for the treatment of AD and other oxidative stress-related diseases.