BACKGROUND: Hyperbilirubinemia (HB) is a common occurrence after cardiopulmonary bypass and often results in increased rates of complications. METHODS: We conducted a study on 411 patients who underwent cardiac surgery with extracorporeal circulation and divided them into a training set and a validation set. Least absolute shrinkage and selection operator (LASSO) regression was employed to screen out variables. Multivariate logistic regression was subsequently applied to establish prediction models, which were then evaluated using receiver operating characteristic (ROC) curves and calibration plots. Finally, restricted cubic splines (RCSs) curve pairs were used to calculate the adjusted ORs for each independent risk factor. RESULTS: A clinical prediction model based on preoperative bilirubin elevation, aortic clamp time and intraoperative red blood cell (RBC) transfusion was successfully developed. The model presented an ROC of 0.855 (0.808, 0.901) in the training set. The validation set demonstrated a promising ROC of 0.839 (0.761, 0.917), and the calibration curve closely approximated the true incidence. The risk of postoperative HB was increased when the aortic clamp time was greater than 133 min, when the red blood transfusion volume was greater than 275 ml or when the preoperative total bilirubin concentration was greater than 16.65 mol/L. CONCLUSION: In this study, the aortic clamp time was identified as a crucial factor for postoperative HB during cardiac surgery. A three-factor prediction model that includes the aortic clamp time for the prediction of HB after cardiac surgery was successfully established. Furthermore, patients with hyperbilirubinemia post-surgery had a worse short-term prognosis.