Acute kidney injury (AKI) is a serious complication of sepsis with a rapid onset and high mortality rate. Bavachin, an active component of Psoralea corylifolia L., reportedly has antioxidant, anti‐apoptotic, and anti‐inflammatory effects; however, its beneficial effects on AKI remain unde‐ termined. We investigated the protective effect of bavachin on lipopolysaccharide (LPS)‐induced AKI in mice and elucidated the underlying mechanism in human renal tubular epithelial HK‐2 cells. Increased serum creatinine and blood urea nitrogen levels were observed in LPS‐injected mice; how‐ ever, bavachin pretreatment significantly inhibited this increase. Bavachin improved the kidney in‐ jury score and decreased the expression level of tubular injury markers, such as neutrophil gelati‐ nase‐associated lipocalin (NGAL) and kidney injury molecule‐1 (KIM‐1), in both LPS‐injected mice and LPS‐treated HK‐2 cells. LPS‐induced oxidative stress via phosphorylated protein kinase C (PKC) β and upregulation of the NADPH oxidase (NOX) 4 pathway was also significantly decreased by treatment with bavachin. Moreover, bavachin treatment inhibited the phosphorylation of MAPKs (P38, ERK, and JNK) and nuclear factor (NF)‐κB, as well as the increase in inflammatory cytokine levels in LPS‐injected mice. Krüppel‐like factor 5 (KLF5) expression was upregulated in the LPS‐treated HK‐2 cells and kidneys of LPS‐injected mice. However, RNAi‐mediated silencing of KLF5 inhibited the phosphorylation of NF‐kB, consequently reversing LPS‐induced KIM‐1 and NGAL expression in HK‐2 cells. Therefore, bavachin may ameliorate LPS‐induced AKI by inhibit‐ ing oxidative stress and inflammation via the downregulation of the PKCβ/MAPK/KLF5 axis.