Objective To investigate the role of Tau‑tubulin kinase 1 (TTBK1) in enriched environment pre‑treatment on sevoflurane‑induced postoperative cognitive impairment in aged mice. Methods According to the random number table method, eighty female C57BL/6J mice with 17‑month‑old age were divided into two groups (n=40): enriched environment (EE) group (EE group) and standard environment (SE) group (SE group). Mice in the two groups were placed in an EE and SE, respectively. Mice in the EE group were pretreated in EE 2 h daily for 4 weeks. Finally, all of the mice grew up to18 months of age and then the EE group and SE group were randomly divided into two groups respectively according to the random number table method (n=20): a SE+control group (SE+C group), a SE+sevoflurane group (SE+S group), an EE+control group (EE+C group), and an EE+sevoflurane group (EE+S group). Mice in the SE+C group only received 60% O2 at 2 L/min for 2 h; those in the SE+S group received 3% sevoflurane plus 60% O2 at 2 L/min for 2 h. Mice in the EE+C and EE+S groups received the same treatment as the SE+C and SE+S groups, respectively. Twenty‑four hours after oxygen or sevoflurane exposure, Morris Water Maze test was conducted to test mouse learning ability and spatial memory for 7 consecutive days through recording escape latency and platform crossing times of 10 mice per group. On that day when mice were treated with oxygen or sevoflurane, the hippocampus tissues of the mice were collected. The expressions of TTBK1, total Tau, AT8, and p‑Ser422 of 5 mice per group were detected by Western blot. The levels of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β, IL‑6 of 5 mice per group were detected by enzyme‑linked immunosorbent assay (ELISA). Results Compared to the SE+C group: mice in the SE+S group showed increased escape latency from Day3 to Day7 and reduced platform crossing times on Day7 (P<0.05). The expressions of TTBK1, AT8, p‑Ser422, TNF‑α, IL‑1β, IL‑6 were significantly increased in the SE+S group (P<0.05). Compared with the SE+S group:the escape latency was decreased from Day3 to Day7 in the EE+S group, and mice in the EE+C group and EE+S group showed increased platform crossing times on Day7 (P<0.05). The EE+C group and EE+S group produced remarkable decreases in the levels of TTBK1, AT8, p‑Ser422, TNF‑α, IL‑1β, and IL‑6 (P<0.05). The total Tau expression in the hippocampus of mice in 4 groups was not statistically significant (P>0.05). Conclusions Pre‑treating mice in EE for 4 weeks can mitigate sevoflurane‑induced postoperative cognitive deficiency in aged mice. The mechanism may correlate with reduced TTBK1 and pathological phosphorylated tau levels caused by EE.