Objective To explore the change of old rats cognitive ability induced by sevoflurane exposure, as well as the role of MyD88/NF-κB signal pathway. Method 20 months of SD rats, male, 550-750g, in accordance with the random number table, were divided into 3 groups (n=15): Control (C group), sevoflurane treatment (S group), and sevoflurane plus ST2825 treatment (IS group). The rats in S and IS groups were subjected to inhale 4% sevoflurane for 6 h, but the rats in C group were inhaled by air-oxygen only. The rats in IS group were injected with ST2825 via lateral ventricle on 10 min before sevoflurane exposure. The cognitive ability was assessed by Morris water maze test and open field test; the activity of NF-κB was assessed by EMSA assay; the expression of hippocampal TNF-α and IL-1β mRNA were assessed by real-time PCR assay; the expressions of Aβ42 were assessed by western blot assay. Result Compared with C group, there were significant increases of escape latency period, the time of the animals spent in the central square, activity of NF-κB, TNF-α mRNA, IL-1β mRNA and Aβ expression but decreases of the number of crossing the grid and the number of standing on the back legs in S group (P<0.05)；Compared with S group, there were significant decreases of escape latency period, the time of the animals spent in the central square, activity of NF-κB, TNF-α mRNA, IL-1β mRNA and Aβ expression but increases of the number of crossing the grid and the number of standing on the back legs in IS group (P<0.05). Conclusion: The cognitive dysfunction of old rats induced by sevoflurane exposure could be associated with activation of MyD88/ NF-κB signal pathway.