Aim To study the effect and mechanism of modified Naotaifang on cerebral ischemia-reperfusion injury of rats by activating SIRT1. Methods Male SD rats were randomly divided into control group, model group, JWF group and JWF+EX527 group. The model of cerebral ischemia-reperfusion injury was established by suture embolization.JWF group was given gavage of modified naotaifang for 14 days, JWF+EX527 group was given gavage of modified naotaifang and intraperitoneal injection of EX527 for 14 days. The differentces of neural function scores, inflammatory factor interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), the expression of Bcl-2, Bax, silent information regulator 1 (SIRT1), nuclear factor-κB(NF-κB) and forkhead box O1(FoxO1) among the four groups were compared. Results Compared with the control group, the neural function scores, the levels of IL-1β, IL-6, TNF-α in serum and brain tissues, the expression of Bax, NF-κB, FoxO1 in brain tissues increased significantly, and the expression of Bcl-2, SIRT1 in brain tissues reduced significantly in the model group(P＜0.05). Compared with the model group, the neural function scores, the levels of IL-1β, IL-6, TNF-α in serum and brain tissues, the expression of Bax, NF-κB, FoxO1 in brain tissues deceased significantly, and the expression of Bcl-2, SIRT1 in brain tissues increased significantly in JWF group(P＜0.05). Compared with JWF group, the neural function scores, the levels of IL-1β, IL-6, TNF-α in serum and brain tissues, the expression of Bax, NF-κB, FoxO1 in brain tissues increased significantly, and the expression of Bcl-2, SIRT1 in brain tissues reduced significantly in JWF+EX527 group(P＜0.05). Conclusion Modified Naotaifang can reduce the cerebral ischemia-reperfusion injury, and activating SIRT1 and then inhibiting NF-κB-mediated inflammatory response, FoxO1-mediated apoptosis was the possible mechanism.