Lipoic acid (LA) is a known antioxidant currently used as a therapy in patients with vascular and metabolic disorders. We tested the hypothesis that lipoic acid is protective against the cell death observed following stroke. Lipoic acid was administered 30 minutes prior to, or immediately following removal of sutures used to occlude the middle cerebral artery (MCA) in male Sprague–Dawley rats. Following removal of the sutures, the MCA territory was allowed to undergo 5.5 hrs of reperfusion. This ischemia/reperfusion (I/R) resulted in a focal infarct restricted to the prefrontal cortex (24 ± 3 mm3). Pretreatment with LA 30 minutes prior to occlusion resulted in a dose-dependent reduction in infarct volume. This reduction in infarct volume was not observed when the LA was administered immediately prior to reperfusion (30 minutes post-occlusion). To investigate a potential hemodynamic mechanism for this LA-induced neuroprotection, blood pressure, heart rate and baroreceptor reflex sensitivity (BRS) were measured. Intravenous administration of LA did not result in any significant changes in any of these parameters compared to saline-treated rats. Similarly, there was no significant contribution of systemic nitric oxide or alteration in cerebral perfusion measured following pretreatment with lipoic acid or during the course of occlusion and reperfusion compared with saline-treated rats. Western blot analysis of tissue from the ischemic cortex showed an increase in protein expression of superoxide dismutase (SOD2), but not SOD1, in LA pretreated rats. This suggests a potential mechanism of action contributing to the LA-induced neuroprotection observed. Furthermore, the data in the present investigation suggest the potential use of LA pretreatment as a neuroprotectant in stroke patients.