Abstract Background Biguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases. Methods The National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model’s performance. Results Of 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%. Conclusion Our results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure.