Abstract Background Prolonged mechanical ventilation (PMV) after cardiac surgery increases the risk of complications such as pulmonary atelectasis and ventilator-associated pneumonia. This study aims to investigate the risk factors associated with delayed extubation, including the impact of cardiovascular medication. Method This retrospective, single-center study analyzed 1,976 patients who underwent open heart surgery at Nanjing Drum Tower Hospital from October 2020 to January 2023. Patients were categorized into early extubation (n = 1071) and delayed extubation (n = 905) groups. Multivariate logistic regression was employed to identify risk factors for delayed extubation. Amiodarone were indicated to be associated with delayed extubation. To further address bias, we derived a propensity score predicting the function of Amiodarone on delayed extubation, and matched 228 cases to 684 controls with similar risk profiles. Results Multivariate analysis confirmed that hypertension, stroke, amiodarone use, age, LVEF, CPB time, and DHCA were significant predictors of delayed extubation. Postoperative use of amiodarone was significantly associated with delayed extubation (OR:1.753, 95%CI: 1.287–2.395, P