Objective To investigate the mechanism of icariin regulating the NLRP3 inflammasome in the treatment of cerebral ischemia-reperfusion injury in rats. Methods A rat model of focal cerebral ischemia-reperfusion was induced using the thread embolism method. At 24 hours post-operation, the rats were randomly allocated into a sham operation group, model group, butylphthalide group (70 mg / kg), ICA-low dose (20 mg / kg), ICA-middle dose (40 mg /kg), and ICA-high dose (80 mg / kg) groups. The corresponding drugs were administered by gavage at 10 mL/ kg once a day for 13 consecutive days. One hour after the last administration, neurological function was scored. The cerebral cortex was observed by hematoxylin-eosin (HE) staining. Expression of interleukin (IL)-1β and IL-18 in the cerebral cortex was determined by immunohistochemistry. Expression of NLRP3, ASC, and Caspase-1 in the cerebral cortex was determined by Western Blot. Results In contrast to the sham operation group, there was a notable increase in neural function scores within the model group. The ischemic area around the visible cerebral cortex showed neuron necrosis at various level or glial cell proliferation, and the number of intact neurons was significantly reduced. IL-1β and IL-18 positive cells were significantly increased. Expression of NLRP3, ASC, and Caspase-1 was significantly increased (P< 0. 01, P< 0. 05).After treatment with icariin, the neural function score was decreased significantly. The degree of neuronal necrosis in the peri-ischemic area was significantly reduced, and the number of intact neurons was significantly increased. IL-1β and IL18-positive cells were decreased significantly. Expressions of NLRP3, ASC, and Caspase-1 were significantly decreased (P< 0. 01, P< 0. 05). Conclusions Treatment of cerebral ischemia-reperfusion injury by icariin may be related to regulation of the NLRP3 inflammasome.