Background: Pleural Mesothelioma (PM) is an unusual, belligerent tumor that rapidly develops into cancer in the pleura of the lungs. Pleural Mesothelioma is a common type of Mesothelioma that accounts for about 75% of all Mesothelioma diagnosed yearly in the U.S. Diagnosis of Mesothelioma takes several months and is expensive. Given the risk and constraints associated with PM diagnosis, early identification of this ailment is essential for patient health. Objective: In this study, we use artificial intelligence algorithms recommending the best fit model for early diagnosis and prognosis of MPM. Methods: We retrospectively retrieved patients clinical data collected by Dicle University, Turkey, and applied multilayered 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 generate 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 a high cost; however, they can identify Mesothelioma with optimal accuracy.