To investigate the effects of dexmedetomidine (Dex) combined with targeted temperature management (TTM) on the expression of hippocampal P2X7 receptor and antisense hypoxia inducible factor (aHIF)‑1α in rats with traumatic brain injury (TBI). Methods A model of TBI was established through controlled cortical impact using rats after 1 week of adaptive feeding. Then, 15 rats were randomly selected as a control group, while the others were set as a model group. The successfully modeled rats were divided into five groups (n=15), according to the random number table method: a sham operation group, a TBI group, a TBI+Dex group, a TBI+TTM group and a TBI+Dex+TTM group. After corresponding treatment, their behaviors were tested, and the expression of tumor necrosis factor (TNF)‑α/interleukin (IL)‑1β in brain tissue and the expression of hippocampal P2X7 receptor and aHIF‑1α were analyzed. Results Rats in each group did not die. Compared with the TBI, TBI+Dex and TBI+TTM groups, the TBI+Dex+TTM group presented remarkably reduced escape latency on Days 3‒5 and shortened exploration duration on Day 6 (P<0.05), as well as decreased expression of TNF‑α and IL‑1β in brain tissues (P<0.05), reduced expression of hippocampal P2X7 receptor and increased amounts of aHIF‑1α (P<0.05). Conclusions Dex combined with TTM can effectively decline the concentration of P2X7 receptor, down-regulate the levels of TNF‑α and IL‑1β, and increase the level of aHIF‑1α, which can be served as a promising therapy for TBI rats.