The Lidanpaidu Prescription (LDP), a hospital preparation, composed of Chinese classical preparations, has been reported to have antiendotoxin, anticoagulant and other effects. However, its therapeutic effect on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and the mechanisms remain unclear. Therefore, we administered LPD pretreatment at different doses to examine the protective effects and mechanisms in LPS-induced AKI in mice. The kidney injury induced by LPS was assessed by histological examination. ELISA was used to detect the levels of inflammatory cytokines. The mRNA expression of the inflammatory genes IKKβ and TNF-α in kidney tissues was assessed by RT-PCR. Finally, Western blot was performed to assess the NF-κB signaling pathway related proteins, and the nuclear translocation of NF-kB P65 was detected by immunofluorescence laser confocal microscopy. The findings suggested that LDP significantly improved at 48 h animal survival (66.7%), compared with the LPS group (26.7%), determined by a Kaplan-Meier analysis. LDP attenuated the kidney histopathological changes induced by LPS and decreased the inflammatory cytokine levels in serum and renal tissue. Moreover, LDP markedly inhibited the expression of inflammatory genes and suppressed the activation of relevant proteins in the nucleus. In summary, these findings suggest that LDP reduces LPS-induced AKI via a mechanism related to the suppression of the NF-κB signaling pathway.