Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid-beta peptide (Aβ), a peptide that as both oligomers and fibrils is believed to play a central role in the development and progress of AD by inducing oxidative stress in brain. Therefore, treatment with antioxidants might, in principle, prevent propagation of tissue damage and neurological dysfunction. The aim of the present study was to investigate the in vivo protective effect of the antioxidant compound ferulic acid ethyl ester (FAEE) against Aβ-induced oxidative damage on isolated synaptosomes. Gerbils were injected intraperitoneally (i.p.) with FAEE or with dimethylsulfoxide, and synaptosomes were isolated from the brain. Synaptosomes isolated from FAEE-injected gerbils and then treated ex vivo with Aβ1–42 showed a significant decrease in oxidative stress parameters: reactive oxygen species levels, protein oxidation (protein carbonyl and 3-nitrotyrosine levels), and lipid peroxidation (4-hydroxy-2-nonenal levels). Consistent with these results, both FAEE and Aβ1–42 increased levels of antioxidant defense systems, evidenced by increased levels of heme oxygenase 1 and heat shock protein 72. FAEE led to decreased levels of inducible nitric oxide synthase. These results are discussed with potential therapeutic implications of FAEE, a brain accessible, multifunctional antioxidant compound, for AD involving modulation of free radicals generated by Aβ.