Hyperthyroidism is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. Sacubitril/valsartan (LCZ696) is a new combined drug that has shown promise for the treatment of hyperthyroidism-associated heart failure; however, the underlying molecular mechanisms, including the contributions of epigenetic regulation, remain unclear. The present study was designed to investigate the therapeutic efficacy of LCZ696 and the potential contributions of microRNA regulation in a rat model of hyperthyroidism-induced cardiac hypertrophy. Cardiac hypertrophy was induced by intraperitoneal administration of levothyroxine. Sixty adults male Wistar rats were randomly allocated to four equal groups (15 rats each): control, cardiac hypertrophy (CH), CH + valsartan, and CH + LCZ696. Treatment with LCZ696 or valsartan significantly improved hemodynamic abnormalities, normalized serum concentrations of natriuretic peptide, fibroblast growth factor-23, and cardiac inflammatory markers compared to CH group rats. Treatment with LCZ696 or valsartan also normalized myocardial expression levels of autophagy markers, fibrotic markers, PPAR-ϒ, mir-377, and let-7b. In addition, both valsartan and LCZ696 ameliorated collagen deposition, ventricular degeneration, and various ultrastructural abnormalities induced by levothyroxine. The beneficial effects of LCZ696 were superior to those of valsartan alone. The superior efficacy of LCZ696 may be explained by the stronger modulation of miR-377 and let-7b.