Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3'-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.