Pleural effusion (PE) is a common clinical complication of many pulmonary and systemic diseases, including lung cancer and tuberculosis. Nevertheless, there is no clinical effective biomarker to identify the cause of PE. We attempted to investigate differential expressed exosomal miRNAs in PEs of lung adenocarcinoma (APE), tuberculous (TPE), and other benign lesions (NPE) by using deep sequencing and quantitative polymerase chain reaction (qRT-PCR). As a result, 171 differentiated miRNAs were observed in 3 groups of PEs, and 11 significantly differentiated exosomal miRNAs were validated by qRT-PCR. We identified 9 miRNAs, including miR-205-5p, miR-483-5p, miR-375, miR-200c-3p, miR-429, miR-200b-3p, miR-200a-3p, miR-203a-3p, and miR-141-3p which were preferentially represented in exosomes derived from APE when compared with TPE or NPE, while 3 miRNAs, including miR-148a-3p, miR-451a, and miR-150-5p, were differentially expressed between TPE and NPE. These different miRNAs profiles may hold promise as biomarkers for differential diagnosis of PEs with more validation based on larger cohorts.