Atrial fibrillation (AF) is the most common sustained arrhythmia associated with significant morbidity and mortality. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. There is growing evidence that oxidative stress is involved in the pathogenesis of AF. Many known triggers of oxidative stress, such as age, diabetes, smoking, and inflammation, are linked with an increased risk of arrhythmia. Numerous preclinical studies and clinical trials reported the importance of antioxidant therapy in the prevention of AF, using vitamins C and E, polyunsaturated fatty acids, statins, or nitric oxide donors. The aim of our work is to give a current overview and analysis of opportunities, challenges, and benefits of antioxidant therapy in AF.