<p>Emerging evidence suggests that long non-coding RNAs (lncRNAs) in the development of chemoresistance in esophageal cancer (EC). In this study, we examined the role of the lncRNA XIST in tumor progression and cisplatin resistance. Transcriptomic profiling of parental (KYSE140) and cisplatin-resistant (CISR) EC cell lines identified XIST as a key regulator associated with the resistant phenotype. Clinical evaluation of EC specimens further revealed significant upregulation of XIST in tumor tissues, particularly in post-neoadjuvant chemotherapy (NACT) and non-responder patient groups. To elucidate its functional significance, Transfection of CISR cells were performed using si-XIST or miR-335-5p mimic, along with respective controls, followed by assessment of proliferation, migration, invasion, and cisplatin sensitivity (<i>p</i> &lt; 0.05). Weighted gene co-expression network analysis (WGCNA) demonstrated a strong association of XIST with epithelial–mesenchymal transition (EMT)-related pathway, while miRNet predicted a regulatory interaction among XIST, miR-335-5p, and ZEB2. The direct binding interactions of miR-335-5p with XIST and ZEB2 were confirmed using dual-luciferase reporter assays and RNA pull-down experiments (<i>p</i> &lt; 0.05). Functional and molecular analyses revealed that XIST promotes tumorigenesis and cisplatin resistance via miR-335-5p sponging, which resulted in the upregulation of ZEB2 and the induction of EMT. Additionally, XIST was found to suppress ferroptosis via the miR-335-5p axis, as confirmed through qPCR, western blotting, iron accumulation, and lipid peroxidation assays (<i>p</i> &lt; 0.05). collectively, these results suggest that the XIST/miR-335-5p regulatory axis plays a pivotal role in EC chemoresistance by enhancing EMT and suppressing ferroptosis, highlighting its potential as a therapeutic target for overcoming treatment resistance.</p> Graphical Abstract <p></p>