Oxidative damage resulting from increased lipid peroxidation (LPO) is considered an important factor in the development of late onset/age-related Alzheimer’s disease (AD). Deuterium-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to the reactive oxygen species-initiated chain reaction of LPO than regular hydrogenated (H-) PUFAs. We investigated the effect of D-PUFA treatment on LPO and cognitive performance in aldehyde dehydrogenase 2 (Aldh2) null mice, an established model of oxidative stress-related cognitive impairment that exhibits AD-like pathologies. Mice were fed a Western-type diet containing either D- or H-PUFAs for 18 weeks. D-PUFA treatment markedly decreased cortex and hippocampus F2-isoprostanes by approximately 55% and prostaglandin F2α by 20–25% as compared to H-PUFA treatment. D-PUFAs consistently improved performance in cognitive/memory tests, essentially resetting performance of the D-PUFA-fed Aldh2−/− mice to that of wildtype mice fed a typical laboratory diet. D-PUFAs therefore represent a promising new strategy to broadly reduce rates of LPO, and combat cognitive decline in AD.