Background: Sacubitril/valsartan effectively treats HFrEF complications by combining vasodilatory and RAAS inhibitory actions. Its effects on myocardial and hepatic stiffness are possibly due to its anti-inflammatory and anti-fibrotic properties but still under study. Objectives: To assess sacubitril/valsartan therapy's impact on myocardial and hepatic stiffness in HFrEF patients. Patients and methods: This prospective cohort study at Qena University Hospitals from March 2023 to February 2024 included 50 HFrEF patients. Clinical examinations, echocardiography, and hepatic stiffness assessment were conducted pre and post-sacubitril/valsartan therapy. Results: Mean age of 49.98 years (±6.98), comprised 20 males (40%) and 30 females (60%), with a mean BMI of 24.69 kg/m^2 (±1.41). None of the participants tested positive for HBsAg or HCV Ab. Pre-management, the ejection fraction (EF) averaged 30.82% (±3.19), significantly increasing to 43.24% (±3.33) post-management (p<0.0001). LVEDD decreased significantly from 60.8 mm (±1.71) to 53.85 mm (±4.32) post-management (p<0.0001). Global longitudinal strain (GLS) improved significantly from -6.16% (±1.75) to -9.44% (±2.62) post-management (p<0.0001). Liver stiffness measurement (LSM) decreased significantly from 7.67 kPa (±1.86) to 6 kPa (±1.39) post-management (p < 0.0001), with a significant decrease in stage F3 fibrosis (p=0.0002). CAP score decreased significantly from 287.2 dB/m (±23.21) to 273.82 dB/m (±28.18) post-management (p<0.0001), with no significant changes in overall steatosis levels. Conclusion: Our findings demonstrates that Sacubitril/valsartan has significant therapeutic benefits in HFrEF, supporting the evidence based guidelines in recommending that patients with HFrEF should be established on Sacubitril/valsartan as one of the “four pillars” of heart failure treatment.