Objective: To investigate the protective effects of formononetin (FN) on the rats with inflammation after focal brain ischemia reperfusion injury. Methods: Sixty adult male SD rats were randomly subjected to either sham surgery, model, FN (8, 16, 32 mg/kg) or nimodipine group (12 mg/kg) for 2 h of brain ischemia and 24 h reperfusion with Longa's score analysis, each with 10. After 24 h of reperfusion, the cerebral infarction volume was determined by TTC staining, and the contents of inflammatory factors in ischemic brain tissue were assayed in each group. In addition, we also examined the changes of nuclear transcription factor-kappaB (NF-κB) and sphingosine kinase 1/sphingosine-1-phosphate (SphK1/S1P) signaling pathway in the ischemic brain tissue. Results: FN each dose group reduced the expression of inflammatory factors, with the inhibition of NF-κB and SphK1/S1P signal pathway significantly. Conclusion: The protective effects of FN on the rats with inflammation after focal brain ischemia reperfusion injury may be related to its inhibition of SphK1/S1P signal pathway.