Centella asiatica (雷公根léi gōng gēn) is a traditional medicinal herb with high antioxidant activity, which decreases amyloid-β (Aβ) deposition in the brain. At the same time, aggregated Aβ-induced oxidative stress is the trigger in the pathogenesis of Alzheimer's disease (AD). Here, we investigated the ability of C. asiatica ethanol extract (CAE) to protect PC12 and IMR32 cells from Aβ_(1-40)-induced production of reactive oxygen species (ROS) and concomitant neurotoxicity. Aggregated Aβ_(1-40) treatment resulted in reduced cell viability, which can be reversed by cotreatment with 25, 50, and 100 μg/mL CAE. Moreover, CAE eliminated the Aβ_(1-40)-mediated increase in ROS production. Thus, CAE-mediated protection against aggregated Aβ_(1-40)-induced neurotoxicity is attributable to modulation of the antioxidative defense system in cells, including the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and levels of glutathione and glutathione disulfide by CAE. This emphasizes the potential therapeutic and preventive value of CAE in the treatment of AD.