Despite the demonstrated advantages of angiotensin receptor/neprilysin inhibitors in the management of heart failure, the pivotal Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure (PARADIGM-HF) trial, which explored this class of medications, did not include individuals from Saudi Arabia. Recognizing that different nations and ethnic groups may exhibit unique characteristics, this study aimed to compare the demographics and outcomes of patients in Saudi Arabia who received sacubitril/valsartan (Sac/Val) with those enrolled in the PARADIGM-HF trial. In this retrospective, multicenter cohort study, we included all adult patients diagnosed with heart failure with reduced ejection fraction (HFrEF) within a tertiary healthcare system in Saudi Arabia between January 2018 and December 2021 and were initiated on Sac/Val. The primary objective was to compare the patient characteristics of those initiating Sac/Val treatment with the participants in the PARADIGM-HF trial. The secondary endpoints included the initiation setting, dose initiation, and titration, as well as alterations in B-type natriuretic peptide and ejection fraction at the 6-month mark. Furthermore, we reported the hospitalization and mortality event rates at the 12-month time point. The study included 400 patients with HFrEF receiving Sac/Val. Compared with the PARADIGM-HF trial, the cohort had a younger mean age and a higher prevalence of diabetes mellitus. SAC/VAL was prescribed as the initial therapy for 34% of the patients, while the remaining participants were initially treated with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker before transitioning to Sac/Val. Approximately 75% of patients were initiated on 100 mg Sac/Val twice daily, and 90% initiated therapy in the inpatient setting. The mean ejection fraction significantly improved from 26.5 ± 8.4% to 30.5 ± 6.4% at 6 months (P < .001), while the median B-type natriuretic peptide level change was not significant (P = .39). Our study revealed notable disparities in the baseline characteristics of patients with HFrEF compared with those in the PARADIGM-HF trial. These findings offer valuable real-world insights into the prescription patterns and outcomes of Sac/Val in patients with HFrEF in Saudi Arabia, an aspect not previously represented in the PARADIGM-HF study.