Sepsis is the complex syndrome characterized by an imbalance between proinflammatory and antiinflammatory response to infection. The brain may be affected during the sepsis, and acute and long-term brain dysfunctions have been observed in both animal models and septic patients. Oxidative stress and antioxidant systems may prove the basis underling brain dysfunction in sepsis. The antioxidant therapy may be theoretically achieved by the following strategies: restoring endogenous antioxidants and nutrients and supplementation with exogenous trace elements, vitamins, and nutrients with antioxidant proprieties; or administering drugs that reduce oxidative stress, such as N-acetylcysteine (NAC), vitamins and statins. In the review, we described below the involvement of oxidative stress and antioxidants defenses and potential utility of these strategies and present data regarding their use in sepsis.