BACKGROUND: Norepinephrine (NE) has been reported to not only regulate cardiovascular activity but also influence inflammatory responses. But its role in sepsis-associated acute kidney injury (SA-AKI) has yet to be elucidated. METHODS: SA-AKI mouse model was induced by intraperitoneally instillation of lipopolysaccharide. After treatment with NE, haemodynamic changes, kidney pathological injury, kidney funcion, systemic and kidney inflammatory responses, were evaluated. Cytokine levels and nuclear factor κB (NF-κB), MAPKs and Akt signalling pathways of macrophages were measured in vitro. Intercellular tight junction and cell viability were detected to evaluate the effect of macrophage inflammatory response on renal tubular epithelium. RESULTS: NE enhanced cardiovascular haemodynamics, alleviated kidney histopathological injury and inflammatory cell infiltration, lowered the levels of kidney cytokines, NGAL, and KIM-1, as well as serum cytokines in SA-AKI mice. In vitro experiments indicated that NE suppressed the secretion of TNF-α, IL-6, and enhanced IL-10 secretion via a mechanism that involves inhibiting NF-κB rather than MAPKs or Akt activation of macrophage, and further alleviated the damage of renal tubule epithelium. CONCLUSION: NE ameliorated SA-AKI via a mechanism that involves inhibiting NF-κB activation to suppress excessive inflammatory responses of macrophages, and improve the injury of renal tubule epithelium, on its basis of improvement of hemodynamic changes in septic mice. CLINICAL TRIAL NUMBER: Not applicable.