Objective To explore the protective effect of naringin on cognitive disorders induced by HIV-1-enveloped glycoprotein 120 (gp120) mediated by the P2X7 receptor in rats. Methods The Morris water maze (MWM) test was used to evaluate the effect of naringin on cognitive dysfunction induced by gp120 intraventricular perfusion in the rat models of dementia. The expression levels of P2X7 receptor mRNA and protein in hippocampus tissues were detected by reverse transcription PCR (RT-PCR) and Western blotting, respectively. Results The MWM test showed that compared with the gp120 model group, the naringin treatment group showed significantly faster escape latencies and reduced searching target errors. RT-PCR and Western blotting showed that the expressions of P2X7 receptor mRNA and protein were reduced in the hippocampus of rats in the naringin treatment group compared with the gp120 model group. Conclusion Naringin may againsts learning and memory dysfunction induced by gp120, which may counter the up-regulated expression of the P2X7 receptor in the hippocampus of rats.