Background <p>This research investigated the expression of microRNA-92a (miR-92a) in chronic heart failure (CHF) patients and assessed its regulatory mechanism using a transverse aortic constriction (TAC) mouse model.</p> Methods <p>Thirty patients with CHF (NYHA class II-IV) and 30 age and sex-matched healthy controls were enrolled from January 2021 to April 2022. Plasma levels of miR-92a were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, we utilized the TAC heart failure mouse model (<i>n</i> = 12) to evaluate the change in cardiac function following adeno-associated virus (AAV) mediated inhibition or overexpression of miR-92a. The following echocardiographic variables were evaluated: ejection fraction (EF), fractional shortening (FS), left ventricular internal diameter diastole (LVIDd), and left ventricular internal diameter systole (LVIDs).</p> Results <p>miR-92a levels were significantly increased in CHF patients and mice following tac application (<i>p</i> &lt; 0.01). Inhibition of miR-92a expression improved cardiac function as evidenced by increased EF and FSs, and decreased LVIDd and LVIDs (<i>p</i> &lt; 0.05).</p> Conclusion <p>miR-92a may serve as a novel diagnostic and therapeutic biomarker for heart failure by altering cardiac remodeling.</p>