Licochalcone A (Lico A), a flavonoid found in licorice root (Glycyrrhiza glabra), has been reported to have anti-inflammatory activity. However, the protective effects of Lico A on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) remains unclear. In this study, using a mouse model of LPS-induced AKI, we investigated the protective effects and mechanism of Lico A on LPS-induced AKI in mice. LPS-induced kidney injury was assessed by detecting kidney histological study, blood urea nitrogen (BUN), and creatinine levels. The production of inflammatory cytokines TNF-alpha, IL-6, and IL-1 beta in serum and kidney tissues was detected by ELISA. The activation of NF-kappa B was measured by western blot analysis. Our results showed that Lico A dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. Lico A also suppressed LPS-induced TNF-alpha, IL-6, and IL-1 beta production both in serum and kidney tissues. Furthermore, our results showed that Lico A significantly inhibited LPS-induced NF-kappa B activation. In conclusion, our results suggest that Lico A has protective effects against LPS-induced AKI and Lico A exhibits its anti-inflammatory effects through inhibiting LPS-induced NF-kappa B activation.