The aim of this study was to evaluate the effect of minocycline preadministration on cognitive dysfunction, hippocampal inflammatory response, and hippocampal senile dementia-related proteins induced by propofol anesthesia in aged rats. Sixty male SD rats, aged 20 months and weighing 340-410 g, were randomly divided into three groups: normal saline (NC) group, propofol group (prop), and minocycline (M) group. Prop group rats were injected intraperitoneally with 100 mg/kg propofol. The rats in group M were injected intraperitoneally with 50 mg/kg minocycline 30 minutes before injection of 100 mg/kg propofol, and the rest were the same as prop group. The rats in NC group were received intraperitoneal injection of the same amount of normal saline. The results indicated that compared with group C, the expressions of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta were upregulated, the levels of TNF-α, IL-1β, and IL-6 were increased, the escape incubation period was prolonged, and the exploration time was shortened in prop group, while the expression of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta in minocycline group was downregulated, the levels of TNF-α, IL-1β, and IL-6 were decreased, the escape incubation period was shortened, and the exploration time was shortened. In conclusion, preadministration of minocycline can improve cognitive impairment induced by propofol anesthesia in aged rats, and its mechanism of action may be related to minocycline inhibiting hippocampal inflammatory reaction and downregulating the expression of GSK-3β, acetyl-NF-κB (Lys310), Tau, and Amlyoid-beta proteins in hippocampus.