Acute kidney injury (AKI) is a common complication following severe sepsis, its incidence is increasing, and it is associated with a high rate of morbidity and mortality. Rutin is a glycoside of the bioflavonoid quercetin with various protective effects due to its antioxidant and anti-inflammatory potential. In this research, we tried to assess the protective effect of rutin administration in a model of AKI in C57BL/6 mice. For induction of AKI, lipopolysaccharide (LPS) was injected once (10 mg/kg, i.p.) and rutin was p.o. given at doses of 50 or 200 mg/kg. Treatment of LPS-challenged group with rutin lowered serum level of creatinine and blood urea nitrogen (BUN), restored to some extent renal oxidative stress-related indices such as malondialdehyde (MDA), glutathione (GSH), and activity of superoxide dismutase (SOD) and catalase. In addition, rutin brought back renal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX2), sirtuin 1 (SIRT1), tumor necrosis factor α (TNFα), interleukin-6, and caspase 3 activity to their control levels. Moreover, protective effect of rutin was in accordance to a dose-dependent manner. Collectively, rutin is capable to mitigate LPS-induced AKI via appropriate modulation of renal oxidative stress, inflammation, and apoptosis.