Backgrounds: Cognitive dysfunction is a complication of anesthesia in surgery. It not only affects the outcome of the surgery, but also increases the patient's mortality rate. This study aimed to investigate the effects of puerarin on cognitive dysfunction in rats after anesthesia with propofol. Methods: Sixty rats were randomly divided into control, model, and low-, middle- and high-dose puerarin groups. The model of cognitive dysfunction after anesthesia was established by intraperitoneal injection of propofol. The low-, medium-and high-dose puerarin groups were intraperitoneally injected with 10, 20 and 40 mg/kg puerarin, respectively. After treatment, animal behaviors were tested. Serum amyloid beta-protein (A beta) and neuron-specific enolase (NSE) levels, hippocampal nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels, hippocampal cAMP-response element binding protein (CREB) and extracellular signal-regulated kinase (ERK) proteins and their phosphorylated forms (p-ERK and p-CREB) were determined. Results: Compared with the model group, in the high-dose puerarin group the escape latency was significantly decreased (P < 0.05), the platform crossing times were significantly increased (P < 0.05), serum A beta and NSE levels were significantly decreased (P < 0.05), hippocampal NGF and BDNF levels were significantly increased (P < 0.05), and p-CREB and p-ERK protein expression levels were significantly increased (P < 0.05). Conclusion: Puerarin can alleviate the cognitive dysfunction after anesthesia in rats, which may be related to its decrease of the A beta and NSE levels, increase of hippocampal NGF and BDNF levels, and increase of hippocampal p-CREB and p-ERK protein expression.