Objective To investigate the effect of sacubitril / valsartan on myocardial injury and cardiac remodeling in rats with heart failure, and to investigate its regulatory effect on transforming growth factor-β1 (TGF-β1) / Smad3 and nuclear factor-κB (NF-κB) signaling pathways. Methods An animal model of heart failure was induced by ligation of the left anterior descending coronary artery in rats. After modelling, rats were treated daily with sacubitril / valsartan at 10 mg / kg (sacubitril / valsartan group, n= 15). Rats in the sham group (n= 15) and the model group (n= 15) were treated with an equal volume of normal saline. Rats were treated for 4 weeks. Echocardiography and histology were used to assess heart function and fibrosis, respectively. Protein levels of TGF-β1, phosphorylated Smad3, phosphorylated Smad7, collagen I, alpha smooth muscle actin, tumor necrosis factor-α, interleukiN-6, NF-κB, and phosphorylated κBα were determined by western blot analysis. Results Left ventricular ejection fraction ( EF) and left ventricular fraction shortening (FS) in the sacubitril / valsartan group were significantly higher, while LVIDs and LVIDd in the sacubitril / valsartan group were significantly lower compared with those in the model group (P< 0. 05). Collagen I expression was significantly reduced in the sacubitril / valsartan group compared with the model group ( P< 0. 05 ). TGF-β1 protein expression and Smad3 phosphorylation levels in the sacubitril / valsartan group were significantly lower, while Smad7 phosphorylation levels were significantly higher compared with the model group (all P<0. 05). Tumor necrosis factor-α and interleukiN-6 protein expression was significantly reduced in the sacubitril / valsartan group compared with the model group ( both P<0. 05). NF-κBp65 and phosphorylated κBα protein expression was significantly reduced in the sacubitril / valsartan group compared with the model group (both P<0. 05). Conclusions Sacubitril / valsartan inhibits myocardial fibrosis and the inflammatory response by inhibiting TGF-β1 / Smad3 and NF-κB signaling pathways in rats with heart failure.