In the current study, we aimed to investigate the mechanistic role of DJ-1/PI3K/Akt survival pathway in ischemia/reperfusion (I/R) induced cerebral damage and to investigate if the Resveratrol (RES) mediates its ischemic neuroprotection through this pathway. RES administration to sham rats, boosted GSH level and SOD activity and downregulated iNOS expression without affecting redox levels of DJ-1 forms nor components of PI3K/Akt pathway including PTEN, p-Akt or p/p-GSK3b. However, RES pre-administration to I/R rats, reduced infarction area, oxidative stress, inflammation and apoptosis. Concomitantly, RES ameliorated the decreased levels of oxidized forms of DJ-1 and enhancing its reduction, increased the nuclear protein expression of Nfr-2 and led to activation of PI3K/Akt survival pathway. In conclusion, overoxidation of DJ-1 is a major factor that contributes to post I/R cerebral damage andits reduction by RES could explain the neuroprotection offered by RSE.