Alzheimer's disease (AD) is a multifactorial neurological disorder in which oxidative stress plays an important role. Diet is closely related to cognition, and at present, there is mounting evidence that certain antioxidant components of diet intake could be beneficial for preventing AD. LMN diet, based on cocoa, nuts, polyphenols, and polyunsaturated fatty acids (patent WO2007063158) has been previously reported to reduce the cardiovascular risk factors common to AD pathology. Herein we report the antioxidant behavior of LMN using SH-SY5Y cell line lesioned with hydrogen peroxide and measuring the expression of the antioxidant enzymes superoxide dismutase-1 and glutathione peroxidase. The signaling pathways involved were also assessed. The antioxidant effect was also demonstrated in hippocampus and plasma of 4-month-old 129S1/SvImJ male mice fed with LMN diet. Integrated metabolome analyses of these tissues and plasma from human subjects after acute consumption of LMN reinforced the importance of oxidative stress, acting possibly through poly (ADP-ribose) polymerase-1 modulation and linoleic acid metabolism.