Abstract: Objective　To investigate the mechanism of microRNA (miR)-134 in post-stroke depression (PSD) by regulating cyclic AMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway. Methods　A total of 32 SD rats were randomly divided into sham operation group, model group, antagomir NC group and miR-134 antagomir group according to the random number table method, with 8 rats in each group. Except for the sham operation group, the other groups were subjected to middle cerebral artery occlusion (MCAO) and then established PSD model induced by chronic unpredictable mild stress (CUMS).  The other operations were the same except that the thread plug was not inserted in the sham operation group. After MCAO, 5 μL (1 μmol/L) antagomir NC and miR-134 antagomir were injected into the brain before CUMS in antagomir NC group and miR-134 antagomir group respectively, once every 5 days for 5 consecutive times. The sham operation group and the model group were injected with equal volume of normal saline. The rats were weighed before CUMS stress, on the 7th, 14th and 21st day after stress, the exercise behavior changes of rats were evaluated by open box test, and pleasure deficiency behavior changes were evaluated by sucrose preference test. At the end of the experiment, the rats were killed and the hippocampal CA1 area was separated, the expressions of miR-134, CREB and BDNF mRNA in hippocampal CA1 area were detected by real-time fluorescence quantitative PCR (qPCR), and the protein expressions of CREB and BDNF in hippocampal CA1 area were detected by immunohistochemical staining. The targeting relationship between CREB and miR-134 was identified by double luciferase reporter gene assay. Results　Compared with the sham operation group, the body mass index of rats, horizontal and vertical activity scores, and the proportion of sugar water drinking were lower in the model group (P＜0.05). Compared with the model group and the antagomir NC group, the body mass index of rats, horizontal and vertical activity score, and the proportion of sugar water drinking were higher in the miR-134 antagomir group (P＜0.05). With the extension of stress time, the effect was gradually obvious. After the experiment, compared with he sham operation group, the level of miR-134 in hippocampal CA1 area was higher in the model group (P＜0.05), and the mRNA and positive cells of CREB and BDNF were lower (P＜0.05). Compared with the model group and the antagomir NC group, the level of miR-134 in hippocampal CA1 area was lower in the miR-134 antagomir group (P＜0.05), and the mRNA and positive cells of CREB and BDNF were higher (P＜0.05). Compared with that of miR-134 mimic NC+CREB-WT, the relative activity of luciferase decreased in miR-134 mimic + CREB-WT co- transfected cells (P＜0.05), indicating that there was a specific binding site of miR-134 in CREB sequence. Conclusion　Down-regulation of miR-134 can promote the expression of CREB/BDNF pathway, and improve depression, so as to protect PSD rats.