Obesity and adipose‐derived peptides might be involved in the pathogenesis of atrial fibrillation (AF). Adiponectin plays a major role in the modulation of several metabolic pathways, and asymmetric dimethylarginine (ADMA) has been suggested to be predictive of AF and associated adverse events. The aim of this study was to investigate the effect of fish oil supplementation on circulating adiponectin and ADMA in overweight or obese patients with persistent AF. In this randomized, double‐blind, placebo‐controlled trial, 80 overweight or obese (body mass index (BMI) ≥ 25 kg/m2) patients with persistent AF were randomly assigned to two groups to receive either 2 g/day fish oil or placebo, for 8 weeks. Serum levels of adiponectin and ADMA, and anthropometric indexes were measured. This study showed that serum adiponectin concentrations increased significantly following fish oil supplementation compared with the placebo group (13.15 ± 7.33 vs. 11.88 ± 6.94 µg/ml; p = .026). A significant reduction was also observed in serum ADMA levels in the fish oil compared with the placebo group following the intervention (0.6 ± 0.13 vs. 0.72 ± 0.15 µmol/L; p = .001). The changes in serum adiponectin and ADMA concentrations remained significant after adjustments for baseline values, age, sex, and changes of BMI and waist circumference (p = .011 and p = .001, respectively). In conclusion, 8 weeks supplementation with fish oil increased serum adiponectin and decreased ADMA concentrations in overweight or obese patients with persistent AF. As adiponectin and ADMA are suggested to be involved in many pathways associated with AF, the current findings might be promising in the clinical management of this disease, an issue that needs further investigations.