Abstract Background Acute kidney injury (AKI) stage 3, one of the most severe complications in patients with heart transplantation (HT), is associated with substantial morbidity and mortality. We aimed to develop a machine learning (ML) model to predict post-transplant AKI stage 3 based on preoperative and perioperative features. Methods Data from 107 consecutive HT recipients in the provincial center between 2018 and 2020 were included for analysis. Logistic regression with L2 regularization was used for the ML model building. The predictive performance of the ML model was assessed using the area under the curve (AUC) in tenfold stratified cross-validation and was compared with that of the Cleveland-clinical model. Results Post-transplant AKI occurred in 76 (71.0%) patients including 15 (14.0%) stage 1, 18 (16.8%) stage 2, and 43 (40.2%) stage 3 cases. The top six features selected for the ML model to predicate AKI stage 3 were serum cystatin C, estimated glomerular filtration rate (eGFR), right atrial long-axis dimension, left atrial anteroposterior dimension, serum creatinine (SCr) and FVII. The predictive performance of the ML model (AUC: 0.821; 95% confidence interval [CI]: 0.740–0.901) was significantly higher compared with that of the Cleveland-clinical model (AUC: 0.654; 95% [CI]: 0.545–0.763, p < 0.05). Conclusions The ML model, which achieved an effective predictive performance for post-transplant AKI stage 3, may be helpful for timely intervention to improve the patient’s prognosis.