Objective To investigate the effect of peroxisome proliferators activate receptor δ (PPARδ) agonist GW501516 on nerve injury after ischemia/ reperfusion (I/R) in rats and its mechanism. Methods A rat model of I/R was established by bilateral common carotid artery clipping combined with hypotension. All rats were divided into Model group (Model) and PPARδ agonist GW501516 intervention group (GW, 5 mg/kg), GW501516+Peroxisome proliferators activate receptor-γ coactivator -1α (PGC-1α) inhibitor SR-18292 group (GW+SR-18292, 5 mg/kg GW501516 combined with 30 mg/kg SR-18292), and sham-operated group (sham), 12 rats in each group. Corresponding drugs were intraperitoneally injected 30 min before modeling, once a day, for 7 consecutive days. Zea-longa score was used to evaluate the neurological function of rats. HE staining was used to observe the histopathological changes of hippocampus. TUNEL staining was used to detect the apoptosis of cells in hippocampal tissue. The content of MDA and the activity of SOD in hippocampus were detected by biochemical method. The copy number of mitochondrial DNA (mtDNA) in hippocampus was detected by qRT-PCR. The protein expressions of PPARδ, PGC-1α, nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) in hippocampus were detected by Western blot. Results Compared with sham group, the Model group rats had severe nerve injury, the apoptosis rate and MDA content of hippocampal tissue were significantly increased (P＜0.05), while SOD activity, mtDNA copy number and protein expression levels of PPARδ, PGC-1α, NRF-1 and TFAM were significantly decreased (P＜0.05). Compared with Model group, the nerve injury of rats in GW501516 group was improved, the apoptosis rate and MDA content of hippocampal tissue were significantly decreased (P＜0.05), while the SOD activity, mtDNA copy number and the protein expression levels of PPARδ, PGC-1α, NRF-1 and TFAM were significantly increased (P＜0.05). However, SR-18292 combined intervention can significantly inhibit the ameliorative effect of GW501516 on nerve injury in I/R rats. Conclusion PPARδ agonist GW501516 can promote mitochondrial biosynthesis, reduce oxidative stress injury, inhibit apoptosis, and improve neural injury after ischemia/reperfusion in rats by upregulating PGC-1α expression