In the present study, we validated the neuroprotective effects of sulfiredoxin 1 (SRXN1) protein against oxidative damage in HT22 cells and ischemic damage in gerbil hippocampus. To deliver SRXN1 protein into cells or hippocampus, PEP-1-SRXN1 fusion protein was synthesized and the efficient delivery was visualized in HT22 cells and gerbil hippocampus. In addition, the treatment of PEP-1-SRXN1 was delivered in HT22 cells with concentration- and incubation time-dependent manners. In addition, PEP-1-SRXN1 treatment significantly ameliorated formation of reactive oxygen species and cell death in HT22 cells induced by H2O2 treatment. In gerbils, PEP-1-SRXN1 treatment significantly alleviated the ischemia-induced hyperactivity 1 day after ischemia and memory deficits 4 days after ischemia. The neuroprotective effects were confirmed by morphological analysis in hippocampal CA1 region 4 or 10 days after ischemia. Treatment with PEP-1-SRXN1 significantly ameliorated the ischemia-induced oxidative stress by reducing glutathione systems in hippocampus. In addition, PEP-1-SRXN1 decreased the ischemia-induced pro-inflammatory cytokine release in the hippocampus. This result suggest that PEP-1-SRXN1 can be potential therapeutics to reduce the neuronal damage induced by oxidative or ischemic damage.