Background <p>Sepsis is a life-threatening systemic inflammatory response triggered by infection. The rapid progression of the disease necessitates early diagnosis and precise intervention, making the identification of reliable biomarkers and therapeutic targets crucial for improving clinical outcomes and reducing sepsis-related mortality.</p> Aim <p>Exploring miR-142-5p as a novel diagnostic biomarker for sepsis and its therapeutic potential via targeting <i>CXCL8</i>.</p> Methods <p>The expression levels of inflammatory factors (IL-6, TNF-α, IL-1β) and miR-142-5p in the serum of patients with sepsis and healthy controls were detected by ELISA and qPCR methods respectively. The diagnostic potential of miR-142-5p was evaluated using Pearson correlation, ROC curve, and logistic regression analyses. Bioinformatic prediction and dual-luciferase assays identified <i>CXCL8</i> as a target, while LPS-induced models and cell transfection experiments investigated miR-142-5p’s therapeutic effects through <i>CXCL8</i> regulation.</p> Results <p>Sepsis patients exhibited significantly decreased miR-142-5p expression, inversely correlating with inflammatory markers (IL-6, TNF-α, IL-1β). ROC analysis showed excellent diagnostic value (AUC = 0.917). Pearson correlations indicated significant clinical associations, while logistic regression identified miR-142-5p as an independent protective factor (HR = 0.498, 95% CI:0.282–0.882, <i>P</i> = 0.017). LPS models confirmed miR-142-5p’s anti-inflammatory effects through cytokine suppression, with knockdown showing opposite effects. Mechanistically, dual-luciferase and transfection assays verified <i>CXCL8</i> as a direct target mediating these effects.</p> Conclusion <p>miR-142-5p may alleviate sepsis by targeting <i>CXCL8</i>-mediated inflammation, suggesting its potential as a diagnostic biomarker and therapeutic target.</p>