Background: Malignant pleural mesothelioma (MPM) is an atypical, belligerent tumor that matures into cancer in the pleura, a stratum of tissue bordering the lungs. Pleural mesothelioma is a common type of mesothelioma that accounts for about 75 percent of all mesothelioma diagnosed yearly in the United States. Diagnosis of mesothelioma takes several months and is expensive. Given the difficulty of diagnosing MPM, early identification is crucial for patient survival. Our study implements artificial intelligence and recommends the best fit model for early diagnosis and prognosis of MPM. Method: We retrospectively retrieved patient’s medical reports generated by Dicle University, Turkey and implemented multi-layered perceptron (MLP), voted perceptron (VP), Clojure classifier (CC), kernel logistic regression (KLR), stochastic gradient decent SGD), adaptive boosting (AdaBoost), Hoeffding tree (VFDT), and primal estimated sub-gradient solver for support vector machine (s-Pegasos). We evaluated the models, compared and tested using paired T-test (corrected) at 0.05 significance based on their respective classification accuracy, f-measure, precision, recall, root mean squared error, receivers characteristic curve (ROC), and precision-recall curve (PRC). Results: In phase-1 SGD, AdaBoost.M1, KLR, MLP, VFDT generates optimal results with the highest possible performance measures. In phase-2, AdaBoost with a classification accuracy of 71.29% outperformed all other algorithms. C-reactive protein, platelet count, duration of symptoms, gender, and pleural protein were found to be the most relevant predictors that can prognosticate mesothelioma. Conclusion: This study confirms that data obtained from biopsy and imagining tests are strong predictors of mesothelioma but are associated with high cost, however, can identify mesothelioma with optimal accuracy. Predictive analytics without using biopsy results can diagnose mesothelioma with acceptable accuracy. Implementation of phase-2 followed by phase-1 can address diagnosis expenses and maximize disease prognosis. Additionally, results indicate improved MPM diagnosis using AI methods dependent upon the specific application.