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Background: Traditional Chinese medicine (TCM) has clear advantages in stabilizing patients with heart failure (HF) and improving cardiac functions. Aims: This study aimed to investigate the role of Cornus officinalis Sieb. et Zucc. (Cor) in HF. Settings and Design: Rats with HF were treated with Cor or Cor with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, dorsomorphin dihydrochloride (Dor). Materials and Methods: The weight and echocardiography findings of the rats were examined. AMPK and p-AMPK expression levels were assessed using Western blots, mitochondrial changes were evaluated using transmission electron microscopy (TEM), and adenosine triphosphate (ATP) levels were detected in each group. Finally, the targets of Cor were analyzed using HERB (http://herb.ac.cn). Statistical Analysis Used: A Student's t- test was used to compare two groups, and a one-way analysis of variance was performed for intergroup comparison. A p < 0.05 indicated that the difference was statistically significant. Results: Compared with that of the Sham group, the body weight of the Model group decreased; left ventricular end diastolic diameter (LVIDd) and left ventricular end systolic diameter (LVIDs) increased; and left ventricular end diastolic posterior wall thickness (LVPWd), left ventricular end systolic posterior wall thickness (LVPWs), left ventricular ejection fraction (EF), and stroke volume (SV) decreased. These effects were reversed by the Cor treatment. Western blot analysis indicated p-AMPK levels were higher in the Model group than those in the Sham group. After Cor treatment, p-AMPK levels increased but later decreased after treatment with Dor. In addition, myocardial mitochondrial abnormalities were reduced and ATP levels increased in the Cor group compared with the Model group, which were reversed by Dor. Lastly, Cor was found to target AMPK pathway-related genes. Conclusion: Cor exerts protective effects on HF by activating AMPK to improve mitochondrial function. [ABSTRACT FROM AUTHOR]