Atrial fibrillation (AF) is a complex arrhythmia with multiple underlying mechanisms, including atrial cardiomyopathy (ACM), which involves structural, electrical, and autonomic dysfunction of the atria. While pulmonary vein isolation (PVI) is a key target for AF ablation, it often fails to prevent recurrent AF in many patients. This review highlights emerging therapeutic strategies targeting ACM, including risk factor modification, epicardial adipose tissue (EAT) reduction, fibrosis, oxidative stress, and the inflammasome. Obesity and other adverse lifestyle factors significantly contribute to AF development and recurrence, and weight loss has shown promise in reducing AF burden. EAT, which is closely associated with the heart, plays a critical role in AF through various mechanisms, including inflammation, fibrosis, and electrical modulation. Targeting EAT with GLP-1 receptor agonists may offer a novel therapeutic approach. Atrial fibrosis, a central feature of ACM, can be mitigated by drugs such as ACE inhibitors, beta-blockers, and TGF-β1 inhibitors. Oxidative stress, driven by reactive oxygen species (ROS), contributes to AF pathogenesis, and targeting ROS production through NOX inhibitors or antioxidants may be beneficial. The NLRP3 inflammasome is also implicated in AF, and inhibitors of this pathway may offer therapeutic potential. Early intervention strategies, including antiarrhythmic drugs and ablation, can prevent AF progression. Despite advances in ablation techniques, non-ablative approaches targeting ACM remain essential for improving AF outcomes. Future research should focus on personalized therapies that address the underlying mechanisms of AF.Atrial fibrillation (AF) is a complex arrhythmia with multiple underlying mechanisms, including atrial cardiomyopathy (ACM), which involves structural, electrical, and autonomic dysfunction of the atria. While pulmonary vein isolation (PVI) is a key target for AF ablation, it often fails to prevent recurrent AF in many patients. This review highlights emerging therapeutic strategies targeting ACM, including risk factor modification, epicardial adipose tissue (EAT) reduction, fibrosis, oxidative stress, and the inflammasome. Obesity and other adverse lifestyle factors significantly contribute to AF development and recurrence, and weight loss has shown promise in reducing AF burden. EAT, which is closely associated with the heart, plays a critical role in AF through various mechanisms, including inflammation, fibrosis, and electrical modulation. Targeting EAT with GLP-1 receptor agonists may offer a novel therapeutic approach. Atrial fibrosis, a central feature of ACM, can be mitigated by drugs such as ACE inhibitors, beta-blockers, and TGF-β1 inhibitors. Oxidative stress, driven by reactive oxygen species (ROS), contributes to AF pathogenesis, and targeting ROS production through NOX inhibitors or antioxidants may be beneficial. The NLRP3 inflammasome is also implicated in AF, and inhibitors of this pathway may offer therapeutic potential. Early intervention strategies, including antiarrhythmic drugs and ablation, can prevent AF progression. Despite advances in ablation techniques, non-ablative approaches targeting ACM remain essential for improving AF outcomes. Future research should focus on personalized therapies that address the underlying mechanisms of AF.