Objective To explore the expression and mechanism of BDNF and TrkB receptors under acute hypoxia and hypoxic preconditioning, and to provide a reference for the study and clinical application of hypoxic preconditioning. Methods A model of acute hypoxia and hypoxic preconditioning was generated in ICR mice. After 0-4days, the hippocampus was isolated from the brains of hypoxic mice, and the protein and gene expressions of BDNF and its receptor TrkB were detected by Western blot and real-time PCR. Results The study found that the tolerance time was increased significantly with the increased amount of hypoxia in mice ( P <0. 05). Compared with the control group, the expression of BDNF and the full-length TrkB receptor in the hypoxia group was increased, and the expression of BDNF protein was significantly increased in the early phase of hypoxic preconditioning ( P <0. 05). Compared with the control group, the expression of the truncated TrkB receptor was decreased, and the expression of mRNA was significantly decreased in the middle and late phase of hypoxic preconditioning ( P <0. 05). Compared with the control group, the activity of the BDNF/ TrkB signaling pathway was inhibited in the acute hypoxia group and increased in the hypoxic preconditioning group. The activity of the BDNF/ TrkB signaling pathway was significantly increased in the late phase ( P < 0. 05).Conclusions Hypoxic preconditioning may be mediated by upregulating the binding between BDNF and TrkB,downregulating the expression of truncated TrkB, reducing the formation of heterodimers, and co-activating the BDNF/ TrkB signaling pathway, which ultimately has a neuroprotective effect in mice.