Background: Malignant mesothelioma (MM) is a lethal tumor of serosal surfaces. Its differentiation from reactive mesothelial hyperplasia is mandatory, and may be problematic in many situations. Thus, the application of a targeted panel of specific markers permits proper diagnosis in the majority of cases. Aim: This study aimed to determine the potential use of BRCA associated protein-1 (BAP1) and CD147 antibodies to differentiate between MM and reactive mesothelial hyperplasia. Materials and Methods: The current work was carried out on 120 cases (56 reactive mesothelial hyperplasia and 64 malignant mesothelioma cases), retrieved as 70 cell blocks and 50 tissue samples. Immunohistochemical staining, using calretinin (to confirm the mesothelial lineage), BAP1, and CD147 antibodies, was performed for each case. Results: Lost nuclear BAP1 expression was detected in 45.3% of the mesotheliomas versus 19.6% of reactive mesothelial hyperplasia cases. Positive membranous CD147 expression was found in 84.4% of mesothelioma cases versus 8.9% of reactive mesothelial hyperplasia cases. BAP1 showed 44.6% sensitivity and 80% specificity, while CD147 showed 84.3% sensitivity and 91% specificity in the diagnosis of malignant mesothelioma. Conclusions: The loss of BAP1 expression and positive CD147 expression could be of diagnostic value for malignant mesothelioma and can exclude the diagnosis of reactive mesothelial proliferations in both biopsy and cytology specimens. CD147 exhibits higher sensitivity and specificity than BAP1.