Background: Atrial fibrillation (AF) is one of the most frequently occurring dysrhythmias after coronary artery bypass graft (CABG) surgery. Aim: The aim of this study was to evaluate the effect of intravenous N-acetylcysteine (NAC) on the prevention of AF after CABG surgery. Methods: In a double-blind, randomised controlled trial, a total of 150 patients who were scheduled for on-pump CABG surgery were randomly assigned into two groups. In group A, patients received an intravenous NAC infusion (50 mg/kg) after induction of anaesthesia. These patients additionally received two intravenous doses of NAC on postoperative days 1 and 2. Patients in group B received normal saline (as a placebo) with the same volume, during the same time interval. During the first three days after surgery, postoperative AF (POAF) was assessed by continuous electrocardiogram monitoring; serum high-sensitivity C-reactive protein (hsCRP) level was also assessed before and three days after surgery. Results: During follow-up, 17 patients (17/141, 12.1%) developed POAF. POAF occurred in four (5.6%) patients in the NAC group and 13 (18.8%) patients in the placebo group (OR 0.23; 95% CI 0.08–0.82; p = 0.02). In the multivariable logistic regression analysis, the only predictor of AF after CABG surgery was the use of NAC (OR 0.21; 95% CI 0.06–0.73; p = 0.01). Also, the hsCRP level trend in the NAC group was different from the trend in the control group (group time interaction or interaction effect) (p < 0.001). Conclusions: It seems that perioperative intravenous NAC therapy can be effectively used to reduce inflammation and the incidence of POAF after CABG surgery. The clinical trial registration number: IRCT2015040921669N1