Aim To observe the clinical efficacy and mechanism of Chaihu Shugan decoction in rats with depression after acute myocardial infarction. Methods 90 models among 120 SD rats were randomly divided into model group(n＝30), Chinese medicine group(n＝30)and fluoxetine group(n＝30), unmodeled rats were normal group(n＝30), after 7 days, 14 days, 21 days for treatment, behavioral indicators were measured in each group of rats, then hippocampus was sacrificed and isolated, and interleukin-1 (IL-1), interleukin-6 (IL-6), cysteinyl aspartate specific proteinase-9 (Caspase-9) and cysteinyl aspartate specific proteinase-3 (Caspase-3) were analyzed by enzyme-linked immunosorbent assay(ELISA), and the expression levels of Jun N-terminal kinase 3 (JNK3) were detected by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Results Compared with normal group in the same period, the behavior indicators of the model group were reduced (P＜0.05), IL-1, IL-6, Caspase-3, Caspase-9, and JNK3 were significantly increased (P＜0.05), while the open-field test scores of Chinese medicine group and fluoxetine group decreased (P＜0.05), and the inflammatory factors were significantly increased in Chinese medicine group and fluoxetine group after 7 days and 14 days (P＜0.05). After 21 days, except IL-1, JNK3, Caspase-9 in Chinese medicine group and IL-1, JNK3 in fluoxetine group, there was no significant difference in the remaining indicators compared with normal group (P＞0.05). Compared with model group in the same period, the behavior indicators were significantly improved in Chinese medicine group and fluoxetine group (P＜0.05), and IL-1, IL-6, Caspase-3, Caspase-9, and JNK3 were significantly reduced (P＜0.05). Compared with fluoxetine group in the same period, IL-1 decreased in Chinese medicine group after 21 days (P＜0.05). Conclusion Chaihu Shugan decoction can effectively improve the depression of myocardial infarction rats, which may be accomplished by inhibiting the inflammation of hippocampus in rats.