Inflammation and oxidative stress play an important role in cerebral ischemic pathogenesis. It has been well established that atorvastatin and probucol could elicit a variety of biological effects through its anti-inflammatory and anti-oxidant properties respectively. This study was to examine whether probucol and atorvastatin in combination had the enhanced protective effect against cerebral ischemia. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). Experiment 1 was used to evaluate the time course expression of Peroxiredoxin2 (Prx2) and Foxo3a after cerebral ischemia. Experiment 2 was used to detect neuroprotective effect of atorvastatin and probucol in cerebral ischemia. At 24h or 72h, neurologic deficit, brain water content and infarct size were measured. Immunohistochemistry, RT-PCR, Western blot and confocal microscope were used to analyze the expressions of Prx2, Foxo3a and nuclear factor erythroid 2-related factor 2 (Nrf2). Compared with the normal-control group, the expressions of Prx2 and Foxo3a were down-regulated in ischemic brain. Compared with the use of probucol or atorvastatin alone, the combined treatment dramatically reduced the brain water content and the infarct volume (P<0.05). Meanwhile, the decrease of Prx2, Foxo3a and Nrf2 was significantly alleviated in combined treatment group. Probucol combined with atorvastatin can get the augmented neuroprotection from the damage caused by MCAO, this effect may be through up-regulation of Prx2, Foxo3a and Nrf2.