Objective To explore the effects of dexmedetomidine on expressions of IL-1 β and TNF-α in hippocampus tissues of aged mice after surgery and postoperative cognitive decline (POCD). Methods A total of 105 aged Kunming mice were randomly divided into 4 groups, i.e. control group (n=15) that received no anesthesia and surgery, anesthesia group (n=30) that received consecutive isoflurane inhalation for 60 min and intraperitoneal injection of ketamine of 100 mg/kg, splenectomized group (n=30) that underwent splenectomy after anesthesia, intervention group (n=30) that received intraperitoneal injection of dexmedetomidine of 15 and 25 μg/kg (15 mice for each dose) 30 min before anesthesia and surgery. Y-maze experiments were conducted 1 d and 3 d after surgery (Y-maze experiments were conducted 3 d after surgery for the intervention group). The trial numbers of each group were recorded. The mRNA and protein expressions of IL-1β and TNF-α in hippocampus tissues were detected by the qRT-PCR and Western blotting. Results The trial number of the anesthesia group was more than that of the control group 1 d after surgery (P<0.05) and was back to normal 3 d after surgery (P>0.05). The trial number of the splenectomized group was more than that of the control group 1 d and 3 d after surgery (P<0.01, P<0.05). The differences of the intervention group and control group 3 d after surgery were not statistically significant (P＞0.05). Compared with the control group, the mRNA and protein expressions of IL-1β and TNF-α of the splenectomized group significantly increased 1 d and 3 d after surgery (P<0.05 or P<0.01), and the differences of the mRNA and protein expressions of IL-1β and TNF-α of the anesthesia group (1 d and 3 d after surgery), intervention group (3 d after surgery), and control group were not statistically significant (P>0.05). Conclusion Pretreatment with dexmedetomidine can decrease the mRNA and protein expressions of IL-1β and TNF-α in hippocampus tissues of mice. The improvement of POCD of mice is relevant to the inhibition of inflammation responses of hippocampus.