Objectives: Sepsis is the most common cause of acute kidney injury (AKI) in patients admitted to the intensive care units. Sepsis-induced AKI (SIAKI) is associated with increased mortality and morbidity in these patients. However, no pharmacological interventions are available to prevent or treat SIAKI. Recent studies have demonstrated that β-Hydroxybutyrate (βOHB) alleviated renal ischemia-reperfusion injury or cisplatin-induced renal injury in a murine model. This study aims to investigate whether βOHB ameliorates the SIAKI in the lipopolysaccharide (LPS)-induced mouse sepsis model. Methods: SIAKI was induced by intraperitoneal LPS injection to C57BL/6 male mice. βOHB was administrated intraperitoneally before LPS injection. The mice were divided into four groups: Control, βOHB, LPS, and βOHB + LPS. Experiments include a quantitative real-time reverse transcription-polymerase chain reaction, western immunoblot, and immunohistochemistry to determine the anti-inflammatory effect and anti-apoptotic effect of βOHB.  Results: The histologic damage score and serum creatinine significantly increased in LPS mice, but were attenuated in βOHB + LPS mice. The expression of tumor necrosis factor-α/interleukin-6/interleukin-1β and the number of F4/80-positive macrophages was lower in βOHB + LPS mice than in LPS mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells and expression of cleaved caspase-3/Bax were lower in βOHB + LPS mice than in LPS mice. Conclusions: Our results show that βOHB pretreatment ameliorates the SIAKI as it reduces tubular apoptosis and inflammatory response. Thus, βOHB pretreatment could be a potential prophylactic strategy against SIAKI.