Background Opioid Use Disorder (OUD) and opioid overdose (OD) impose huge social and economic burdens on society and health care systems. Research suggests that Medication for Opioid Use Disorder (MOUD) is effective in the treatment of OUD. We use machine learning to investigate the association between patient’s adherence to prescribed MOUD along with other risk factors in patients diagnosed with OUD and potential OD following the treatment. Methods We used longitudinal Medicaid claims for two selected US states to subset a total of 26,685 patients with OUD diagnosis and appropriate Medicaid coverage between 2015 and 2018. We considered patient age, sex, region level socio-economic data, past comorbidities, MOUD prescription type and other selected prescribed medications along with the Proportion of Days Covered (PDC) as a proxy for adherence to MOUD as predictive variables for our model, and overdose events as the dependent variable. We applied four different machine learning classifiers and compared their performance, focusing on the importance and effect of PDC as a variable. We also calculated results based on risk stratification, where our models separate high risk individuals from low risk, to assess usefulness in clinical decision-making. Results Among the selected classifiers, the XGBoost classifier has the highest AUC (0.77) closely followed by the Logistic Regression (LR). The LR has the best stratification result: patients in the top 10% of risk scores account for 35.37% of overdose events over the next 12 month observation period. PDC score calculated over the treatment window is one of the most important features, with better PDC lowering risk of OD, as expected. In terms of risk stratification results, of the 35.37% of overdose events that the predictive model could detect within the top 10% of risk scores, 72.3% of these cases were non-adherent in terms of their medication (PDC <0.8). Targeting the top 10% outcome of the predictive model could decrease the total number of OD events by 10.4%. Conclusions The best performing models allow identification of, and focus on, those at high risk of opioid overdose. With MOUD being included for the first time as a factor of interest, and being identified as a significant factor, outreach activities related to MOUD can be targeted at those at highest risk.