e23086 Background: It is anticipated that implementing machine learning (ML) strategies will impact the clinical decision-making process in the future. This study aimed to compare the accuracy of various machine learning algorithms in predicting suicidal ideation in patients who were receiving treatment for prostate cancer (PC). Further, to predict suicidal ideation and explain the burden of illness (BOI) by utilizing ML algorithms and XAI-based interpretability. Methods: We analyzed the United States 2017 National Inpatient Sample database for patients hospitalized for PC using linear and non-linear ML methods. Using techniques such as forward selection (FS) and backward elimination (BE), Random Forest (RF), decision trees, Multivariate Adaptive Regression Splines, and Gradient Boosting Machine (GBM), we determined subsets and features. We used linear and non-linear MLs-- Lasso, Ridge, RF, and Neural Networks (NN). A 70% and 30% partitioning was performed on the training and test datasets. The performance of the model was tested using discrimination (C-statistics), the Receiver-Operating Characteristics (ROC) curve, and the Hosmer-Lemeshow tests on both the training data and the test data. Several XAI approaches, including permutation significance, global surrogate marker, feature interpretation, interactivity, and local interpretability, were also utilized to examine the BOI (Length of stay (LOS)) among PC cancer cohort with suicide ideation. Results: We identified 680 patients with suicidal ideation among 208,730 PC patients. The most important variable derived through FS and BE were depression, drug abuse, psychiatric disorder, alcohol dependence, race, Medicaid beneficiaries, cardiac arrhythmias, metastasis, weight loss, congestive heart failure, and un-complicated hypertension, further confirmed through the GBM and other methods. There was successful documentation of demographic, socioeconomic, and clinical characteristics through feature selection approaches. Linear models, Lasso, and Ridge demonstrated an excellent area under the ROC for all cohorts ( > 0.9 in train and test datasets). On the other hand, tree-based models, such as RF, performed poorly (AUC 0.72 for train and 0.66 for test). The findings of the XAI methodologies showed that among PC suicide ideation, higher BOI was associated with patients staying in low-income neighborhoods, Whites, Medicaid beneficiaries, and those with weight loss. Conclusions: We showcase the increasing capability of predictive analytics, particularly XAI, in predicting suicidal ideation. The combination of the vast amount of data generated by the digitalization of healthcare systems with the advanced processing power of modern servers enables the development of machine learning-based care pathways, which has the potential to revolutionize clinical decision-making in cancer.