<p>Cisplatin resistance remains a major limitation in the treatment of non-small cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs), particularly metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), have been implicated in tumor progression and drug resistance, although the underlying mechanisms are not fully understood. Expression of MALAT1 and miR-20b-5p was analyzed in NSCLC datasets from GEO and validated in parental A549 and cisplatin-resistant A549/DDP cells. Cell viability, apoptosis, migration, cell cycle distribution, and caspase-3/7 activity were evaluated after MALAT1 knockdown or miR-20b-5p overexpression/inhibition. Molecular interactions were examined using dual-luciferase reporter assays. STAT3 signaling and multidrug resistance proteins were assessed by western blotting, and STAT3 inhibition was performed using niclosamide. MALAT1 was significantly upregulated, whereas miR-20b-5p was downregulated, in NSCLC tissues and A549/DDP cells. Mechanistically, MALAT1 acted as a competing endogenous RNA that sponges miR-20b-5p, thereby enhancing STAT3 signaling. Silencing MALAT1 or restoring miR-20b-5p suppressed STAT3 activation and reduced MDR1 and MRP1 expression. Functionally, MALAT1 knockdown increased cisplatin sensitivity, promoted apoptosis, inhibited proliferation and migration, and induced G1 arrest in A549/DDP cells. These effects were largely reversed by miR-20b-5p inhibition. Pharmacological STAT3 inhibition reproduced the effects of MALAT1 silencing. The MALAT1/miR-20b-5p/STAT3 axis promotes cisplatin resistance in A549/DDP NSCLC. These findings identify the MALAT1/miR-20b-5p/STAT3 axis as a potential regulator of cisplatin resistance in A549/DDP NSCLC cells and provide a basis for future translational investigation.</p>