Pleural mesothelioma (PM), an uncommon yet highly aggressive malignant neoplasm, has a very poor prognosis with a median survival of less than one year after diagnosis, morbidity and mortality due to PM are on the rise year by year worldwide. Our research aims to utilize molecular characteristics and microRNAs (miRNAs) as a breakthrough in predicting the survival of PM patients, hoping to find a molecular mechanism that can predict the survival of PM patients. The miRNA expression profiles and corresponding clinical information of patients with PM were obtained from The Cancer Genome Atlas (TCGA) database, a miRNA-based prognostic signature was developed using Cox regression analysis in the training cohort, which was validated in the testing cohort and complete cohort. The association between miRNA levels and survival outcomes was determined, the miRNAs in prognostic model were experimentally validated by quantitative real-time PCR (qRT-PCR) in cell lines. Target genes of prognostic miRNAs were identified using TargetScan, miRDB, and miRTarBase databases, biological function prediction of which was accomplished by GO and KEGG analysis. Gene Expression Omnibus (GEO) database was utilized for core targets recognition, immune infiltration and survival analysis were conducted to investigate the relationship between core targets and immune cells by bioinformatics analysis. This miRNA-related prognostic risk model can effectively stratify patients into high-risk and low-risk groups, and have good sensitivity and specificity to assess the prognosis of patients with PM, which can also be used as an independent prognostic factor for overall survival (OS) prediction in patients with PM, the OS for patients in high-risk group was significantly poorer compared with patients in low-risk group. Moreover, all four miRNAs (hsa-miR-181a-2-3p, hsa-miR-491-5P, hsa-miR-503-5p, and hsa-miR-3934-5p) were found to be differentially expressed in PM cell lines as compared with normal cell line, GO and KEGG analysis revealed that target genes of miRNAs in prognostic model were involved in multiple tumor-associated signaling pathways and functions in PM, core miRNA targets also correlated with immune cell infiltration, indicating their potential role in PM initiation and progression. A robust four-miRNA prognostic signature with great performances in prediction of the OS for PM patients was developed in our study, providing new avenues for the prognostic predication of PM.