Aim To observe the effect of butylphthalide (NBP) injection on the expression of the neuronal apoptosis, SIRT1 and PGC-1α in hippocampus CA₁ of rats with focal cerebral ischemia-reperfusion, then explore the mechanisms of neuroprotection from NBP. Methods 160 male SD rats were randomly divided into sham group, middle cerebral artery occlusion group (MCAO group), high dose NBP post-treatment group (high dose group), middle dose NBP post-treatment group (middle dose group) and low dose NBP post-treatment group (low dose group). Focal cerebral ischemia reperfusion model was established with the improved Zea Longa method. The later four groups were further divided into 6 h, 12 h, 24 h, 48 h and 72 h point after model. TUNEL staining was used to observe the expression of neuronal apoptosis. Immunohistochemistry and quantitative real-time PCR were used to observe the expression of SIRT1 and PGC-1α. Results Compared with MCAO group, the number of apoptotic cells were significantly decreased and the number of SIRT1 and PGC-1α positive cells were significantly increased in NBP post-treatment group at each time point (P＜0.05).Compared with low dose and middle dose group, the number of apoptotic cells were significantly decreased and the number of SIRT1 and PGC-1α positive cells were significantly increased in high dose group (P＜0.05). Compared with low dose group, the number of SIRT1 positive cells were significantly increased except for 6 h and the number of PGC-1α positive cells were significantly increased except for 6 h and 72 h in middle dose group at related point (P＜0.05). Compared with MCAO group, the expression of SIRT1 and PGC-1α mRNA were significantly increased in high dose group at each time point (P＜0.05). Conclusion The findings demonstrate that NBP can inhibit cell apoptosis and relieve the brain damage of focal cerebral ischemia reperfusion in rats, which may significantly associate with the up-regulating of SIRT1 and PGC-1α.