BACKGROUND: Cisplatin (DDP) is a commonly utilized chemotherapeutic agent. Nevertheless, the development of resistance to DDP significantly diminishes the effectiveness of DDP-based chemotherapy in patients with non-small cell lung cancer (NSCLC). In this study, we investigated the impact of endothelin 1 (EDN1) on the resistance to DDP in NSCLC. METHODS: The proliferation, invasion, and migration of NSCLC cells were detected by cell counting kit-8 and Transwell migration and invasion assays. ELISA was performed to analyze the inflammatory cytokines concentrations. The related protein levels of tumor necrosis factor (TNF) signaling pathway were analyzed by Western blot. Besides, a xenograft tumor mice model was established to explore the role of EDN1 in vivo. RESULTS: The results showed that DDP-resistance upregulated EDN1 expression, cell viability, invasion, migration, and inflammation in NSCLC cells, while the results were reversed after EDN1 inhibition. EDN1 affected DDP-resistance of NSCLC by regulating TNF signaling pathway. Overexpression of TNF receptor-1 (TNFR1) reversed the decreased cell viability, invasion, migration, and inflammation induced by silencing EDN1 in A549/DDP cells. Moreover, silencing EDN1 inhibited tumor growth and the protein levels of EDN1 and TNFR1. CONCLUSION: EDN1 promoted DDP resistance in NSCLC cells through the modulation of the TNF signaling pathway, suggesting a potential therapeutic intervention strategy for NSCLC.