BACKGROUND: Sepsis, a systemic inflammatory disease, often leads to severe complications, including septic acute kidney injury (AKI). Despite its prevalence, effective treatments for septic AKI remain elusive. MicroRNAs (miRNAs) are critical regulators of gene expression and play essential roles in sepsis pathogenesis. This study investigates the function and regulatory pathway of miR-760 in septic AKI. METHODS: Septic AKI models were developed using lipopolysaccharide (LPS)-treated mice and HK-2 renal tubular epithelial cells. Renal pathology was assessed via H&E staining, while renal function was assessed through the measurement of blood urea nitrogen (BUN) and creatinine levels. Apoptosis, inflammation, and oxidative stress markers were analyzed using functional assays, ELISA, and flow cytometry. Bioinformatics analysis, RT-qPCR, and dual luciferase reporter assays were used to identify and validate miR-760's target, enkurin domain containing 1 (ENKD1). RESULTS: Database analysis and experimental validation revealed markedly decreased level of miR-760-3p levels in LPS-induced septic AKI mice model. MiR-760-3p overexpression in vivo ameliorated renal damage, improved kidney function, and reduced tubular apoptosis, inflammation, and oxidative stress. In vitro, miR-760 mimics enhanced cell proliferation while inhibiting apoptosis, inflammation, and oxidative stress in LPS-stimulated HK-2 cells. Mechanistically, ENKD1 was identified as a direct target of miR-760. ENKD1 overexpression negated the protective effects of miR-760, exacerbating renal injury, apoptosis, and inflammatory responses. CONCLUSION: This study demonstrates that miR-760 alleviates septic AKI by targeting ENKD1, reducing apoptosis, inflammation, and oxidative stress. The miR-760/ENKD1 axis offers a promising therapeutic avenue to address septic AKI.