Background <p>To investigate the diagnostic and prognostic value and regulatory role of LINC00278 in severe pneumonia.</p> Methods <p>A total of 312 volunteers were enrolled with a follow-up period of 90 days. Blood and bronchoalveolar lavage fluid samples from participants were stored at −80 °C. ROC curves, KM curves, and multivariate Cox regression analyses assessed LINC00278‘s diagnostic and prognostic utility. RT-qPCR examined gene expression; CCK-8 assays evaluated cell proliferation. ELISA measured inflammatory cytokine expression, while commercially available kits quantified oxidative stress levels. DLR and RIP validated gene-target relationships.</p> Results <p>LINC00278 was upregulated in both blood and bronchoalveolar lavage fluid samples from patients with severe pneumonia. Elevated LINC00278 expression predicted poorer patient outcomes. LPS treatment promoted LINC00278 expression in pulmonary epithelial cells, slowed cell proliferation, and increased inflammatory and oxidative stress levels. miR-149-5p was downregulated in critically ill patients and identified as a target gene of LINC00278. The miR inhibitor reversed the cellular functions and inflammatory levels modulated by si-LINC00278. Forty-nine genes were identified as potential downstream targets of the LINC00278/miR-149-5p pathway.</p> Conclusions <p>LINC00278 impairs pulmonary epithelial cell proliferation by suppressing miR-149-5p, elevating cellular inflammation and oxidative stress levels, thereby contributing to poor prognosis in critically ill pneumonia patients.</p> Clinical trial number <p>Not applicable.</p>