Endothelin (ET)-1 is involved in various fibrotic diseases. However, its implication in pleural fibrosis remains unknown. We aimed to study the profibrotic role of ET-1 in tuberculous pleural effusion (TBPE). The pleural effusion ET-1 levels were measured among 68 patients including transudative pleural effusion (TPE, n = 12), parapneumonic pleural effusion (PPE, n = 20), and TBPE (n = 36) groups. Pleural fibrosis, defined as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Additionally, the effect of ET-1 on mesothelial mesenchymal transition (MMT) and extracellular matrix (ECM) producion in human pleural mesothelial cells (PMCs) was assessed. Our findings revealed that effusion ET-1 levels were significantly higher in TBPE than in TPE and PPE, and were markedly higher in TBPE patients with RPT >10 mm than those with RPT ≤10 mm. ET-1 levels correlated substantially with residual pleural shadowing and independently predicted RPT >10 mm in TBPE. In PMCs, ET-1 time-dependently induced MMT with upregulation of α-smooth muscle actin and downregulation of E-cadherin, and stimulated ECM production; furthermore, ET receptor antagonists effectively abrogated these effects. In conclusion, ET-1 induces MMT and ECM synthesis in human PMCs and correlates with pleural fibrosis in TBPE. This study confers a novel insight into the pathogenesis and potential therapies for fibrotic pleural diseases.