OBJECTIVE: To compare the efficacy of amiodarone alone versus amiodarone combined with sacubitril/valsartan in patients with new-onset atrial fibrillation (NOAF) after acute myocardial infarction (AMI) and to provide a theoretical basis for optimizing clinical strategies. METHODS: Data of 106 NOAF patients admitted to West China Hospital, Sichuan University (January 2022 to June 2024) were retrospectively analyzed. Patients were divided into a control group (amiodarone alone) and an observation group (amiodarone combined with sacubitril/valsartan). Demographic characteristics, length of hospital stay, duration of atrial fibrillation, creatine kinase MB (CK-MB), high-sensitivity cardiac troponin T (hs-cTnT), ventricular rate, creatinine, urea, C-reactive protein (CRP), alanine transaminase (ALT), and aspartate aminotransferase (AST) were collected and compared between the two groups. Cardiac function parameters, including left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LVESD), recurrence rate, and other adverse events, were recorded at admission and six months post-discharge. RESULTS: Both groups showed significant improvement in CK-MB, hs-cTnT, ventricular rate, ALT, and AST after treatment, with no significant difference between the groups. While CRP levels remained stable in the control group, the observation group demonstrated a significant decrease. Additionally, the observation group showed a significantly elevated LVEF level but lower LVESD and LVEDD levels after treatment, while these parameters remained unchanged in the control group. Besides, the observation group had a longer recurrence time and a lower incidence of stroke. CONCLUSION: Amiodarone combined with sacubitril/valsartan significantly improves cardiac function, prolongs the time to recurrence, and reduces the incidence of stroke in NOAF patients after AMI.