Abstract Background Atrial fibrillation (AF) ablation has become an established therapeutic modality for rhythm control. However, the optimal post-ablation pharmacological strategy remains uncertain. The present study addresses this gap by conducting a comparative analysis of four commonly used antiarrhythmic drugs (amiodarone, propafenone, sotalol, and flecainide), both as standalone treatments and in combination with beta blockers, to determine their impact on mortality, hospitalization rates, and AF recurrence. Methods A multi-center, retrospective cohort study was conducted, including patients who underwent successful AF ablation between 20010 to 2020. The study population was divided into groups based on the prescribed antiarrhythmic drug regimen: amiodarone, propafenone, sotalol, flecainide, and respective combinations with beta blockers. Patient demographics, comorbidities, and procedural details were collected. Endpoints included all-cause mortality, hospitalization due to cardiovascular events, MACE and AF recurrence. Results A total of 908 patients were included in this study. The mean age was 66 years old, and 33% (n=297) were female patients. Of 908 patients, 35% (n=316) were prescribed amiodarone, 34% (n=305) propafenone, 8% (n=76) sotalol, and 6%% (n=51) flecainide post AF ablation. Association with beta blockers were observed in 55% (n=496) of cases. Amiodarone group had a 0,3% (n=1) mortality, 9% (n=27) of hospitalizations, 2% (n=5) of major cardiovascular events (MACE) and 32% (n=101) of AF recurrence. Propafenone group had a 1,3% (n=4) mortality, 4% (n=12) hospitalizations, 2% (n=5) of MACE and 27% (n=81) of AF recurrence. Sotalol group had a 4% (n=3) mortality, 6% (n=4) of hospitalizations, 3% (n=2) of MACE and 44% (n=32) of AF recurrence. Flecainide group had 0 cases of death, 2% (n=1) of hospitalization, 0 cases of MACE and 35% of recurrence. Amiodarone is associated with a lower risk of death (p=0,018 OR 0,13). The presence of betablockers did not affect the endpoints, namely, death, hospitalization, MACE or AF recurrence. There were no other statistically significant associations between variables. Conclusion This study evaluated the effectiveness of common antiarrhythmics, such as amiodarone, propafenone, sotalol, and flecainide, with and without beta blockers, in the post-AF ablation setting. In this study, amiodarone showed a lower risk of death. There were no other statistically significant associations between either antiarrhythmic drug and each endpoint. The presence of betablocker therapy did not interfere with the endpoints. The findings contribute to the ongoing discourse on the optimal pharmacological strategy for AF management post-ablation. Further prospective studies with larger sample sizes are warranted to validate and refine these observations, paving the way for evidence-based guidelines in tailoring antiarrhythmic drug regimens for improved patient outcomes