Septic acute kidney injury (AKI) is a frequent and serious complication of sepsis in critically ill patients associated with high morbidity and mortality. However, the treatment of septic AKI has still been beyond satisfaction. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin and is proposed as a potential agent for treating cancer and inflammatory diseases. In the present study, we aimed to investigate the effect of DHA on lipopolysaccharide (LPS)-induced AKI and the underlying mechanism. Male C57BL/6 mice were pretreated with or without DHA (20 mg/kg/d) for two days, and then were treated with one dose LPS (10 mg/kg) intraperitoneal injection to induce septic AKI. Twenty-four hours after LPS injection, blood samples and kidneys were collected for evaluation. The results indicated that DHA significantly ameliorated LPS-induced AKI as evidenced by improvement of renal function (serum creatinine and blood urea nitrogen), amelioration of renal pathological injury, and inhibition of tubular cell apoptosis. Meanwhile, DHA also strikingly attenuated inflammatory response, suppressed NF-κB signaling pathway activation, and inhibited oxidative stress in LPS-challenged mice. In conclusion, DHA could protect against LPS-induced AKI possibly by anti-inflammatory and antioxidant activities.