Objective This study aims to investigate the functional role of long non-coding RNA lincRNA-COX2 in the in vivo mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the in vitro injury model of mouse lung epithelial MLE-12 cells, and to elucidate the molecular mechanism by which it regulates ferroptosis. Methods In vivo animal experiments were performed with mice assigned to the control group and LPS model group (n=12 per group). In vitro cellular experiments included four groups: control group, LPS model group, sh-lincRNA-COX2 + LPS group, and Erastin co-treatment group, which were set up for reverse functional validation. An ALI mouse model was established by intranasal instillation of LPS, and an in vitro injury model was constructed by stimulating mouse lung epithelial cells (MLE-12) with LPS. Pathological changes in lung tissue, apoptosis, and iron deposition were assessed using hematoxylin-eosin (H&E) staining, TUNEL staining, and Prussian blue staining, respectively. The expression level of lincRNA-COX2 was detected by quantitative real-time PCR (qRT-PCR). Cell viability and apoptosis rate were measured using the CCK-8 assay and flow cytometry, respectively. Levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative stress markers (8-OHdG, MDA, CAT, SOD, GSH-Px) were determined by ELISA. Western blotting was used to analyze the Nrf2/HO-1 signaling pathway and ferroptosis-related proteins (GPX4, SLC7A11, ACSL4). Results Lung tissues of ALI mice showed structural damage, inflammatory cell infiltration, increased apoptosis, and iron deposition, along with significantly upregulated lincRNA-COX2 expression. Similarly, LPS induced high expression of lincRNA-COX2 in MLE-12 cells. Functional experiments demonstrated that knockdown of lincRNA-COX2 significantly improved cell viability, suppressed apoptosis, and alleviated inflammation and oxidative stress induced by LPS. Mechanistic studies revealed that lincRNA-COX2 knockdown promoted nuclear translocation of the transcription factor Nrf2, upregulated the expression of its downstream target protein HO-1, and subsequently regulated key ferroptosis-related proteins (upregulating GPX4 and SLC7A11, downregulating ACSL4), ultimately inhibiting ferroptosis. Conclusions This study demonstrates that lincRNA-COX2 exacerbates oxidative stress and promotes ferroptosis in lung epithelial cells by inhibiting the Nrf2/HO-1 signaling pathway, thereby contributing to the pathogenesis of ALI. Targeted inhibition of lincRNA-COX2 may provide a potential therapeutic strategy for the prevention and treatment of ALI.