Alpha-lipoic acid (ALA) and vitamin E (VE) are normally present in human diet and their side-effects derived from oral supplementation are very rare. Interestingly, a combination of these antioxidants has shown synergistic effects, as determined in experimental and clinical studies. This chapter summarizes (1) The role of oxygen free radicals in brain injuries; (2) The antioxidant effects of ALA and VE in the brain; (3) The mechanism of action of the synergy between ALA and VE; and (4) The increasing evidence showing that the combination of ALA and VE is more effective than any antioxidant mono for reducing oxidative damage. Specifically, ALA and VE efficiently counteract oxidant radicals in a number of neurological diseases, such as brain ischemia, Parkinson’s disease, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, diabetic neuropathy, and Alzheimer’s disease. Yet, ALA and VE are also effective in non-neurological diseases, such as rheumatoid arthritis, chemo , high performance exercise, cataracts, heart failure, myocardial infarction, atherosclerosis, chronic fatigue syndrome, and aging process. In summary, although antioxidants by themselves cannot prevent the incidence of neurological diseases, they can delay its occurrence and/or reduce the magnitude of neural damage. Therefore, diets or commercial supplements enriched with these two antioxidants may be ideal for people in risk of suffering from neurological conditions generated by unbalance production of oxygen free radicals.