Sepsis is the main cause of acute kidney injury (AKI), mainly due to systemic immune dysregulation. Kaempferol (KAE) is a natural flavonoid compound with multiple biological activities including anti-inflammatory, antioxidant, and antiapoptotic properties. In this study, we constructed a sepsis-induced AKI mouse model and an LPS-induced glomerular mesangial cell (HK-2) in vitro sepsis AKI model. We found that KAE ameliorated sepsis-induced renal pathological damage, reversed renal function damage, and inhibited p-p65 and p-AKT protein expression. In addition, KAE reversed LPS-induced proliferation and inhibited apoptosis in HK-2 cells. These studies suggest that KAE reverses sepsis by inhibiting activation of the NF-κB/AKT pathway to reverse acute kidney injury.