To date, despite improvement in survival rate following a Fontan operation, postoperative prolonged pleural effusion (PPE) has still remained a confounding complication of this procedure, which significantly contributes to morbidity and prolonged hospitalization. Our study aims to investigate risk factors associated with PPE after the extracardiac Fontan operation. From August 2012 to December 2019, we obtained clinical data from the medical records of 145 consecutive patients who were diagnosed with single-ventricle lesions and received an extracardiac Fontan operation at the E Hospital (Hanoi, Vietnam). PPE was defined as the need for a chest tube for > 14 days. Patients were divided into two groups, those with PPE (n = 29, 20.00%) and those without PPE (n = 116, 80.00%). During the pre-Fontan evaluation, significant differences between two groups were observed in PPE (p = 0.00), chylothorax (p = 0.045), pleurodesis (p = 0.045), position of thoracic and abdominal organs (p = 0.018), atrioventricular (AV) valve regurgitation (p = 0.030), and large aortapulmonary circulation (p = 0.041). During the Fontan evaluation, significant differences among two groups were seen in aortic cross-clamp time (p = 0.04), cardiopulmonary bypass time (p = 0.014), and mean pulmonary artery pressure (PAP) at Fontan (p = 0.0072). In multivariable analysis with logistic regression, a reduced model including independent predictors for PPE was found to be the NYHA class III (OR 4.93, 95% CI 1.19–20.50, p = 0.028), double-outlet right ventricle (DORV) with transposition of great arteries (TGA) (OR 31.00, 95% CI 1.35–711.63, p = 0.032), AV valve regurgitation (OR 70.73, 95% CI 3.28–1523.28, p = 0.007), ventricle-to-pulmonary artery shunt (OR 8.29, 95% CI 1.60–42.78, p = 0.012), PAI (OR 0.98, 95% CI 0.97–0.99, p = 0.002) at pre-Fontan, while, at Fontan, high PAP (OR 1.24, 95% CI 1.01–1.53, p = 0.046) was an independent predictor for PPE. In conclusion, the incidence of PPE was relatively low. The NYHA class III, primary anatomical diagnosis of DORV with TGA, pre-Fontan AV valve regurgitation, the existence of pre-Fontan ventricle-to-pulmonary artery shunt, low pulmonary artery index (PAI), and high PAP in the operation were identified as independent risk factors to predict PPE following a Fontan operation. As prior studies also investigated various risk factors influencing PPE, a preventive strategy that targets these factors combined with previous identified other risk factors might reduce the PPE incidence.