This study aims to investigate the renal protective effect and mechanism of Panax notoginseng saponins (PNS) on sepsis-associated acute kidney injury (SA-AKI) mice. C57BL/6 mice were randomly separated into a control group, a model group, an iron death inhibitor ferrostatin-1 group (Fer-1), PNS low dose group (PNSL), PNS high dose group (PNSH), and a PNS high dose+ML385 group (PNSH+ML385) using a random number table method, with 12 mice in each group. The SA-AKI model was established by intraperitoneal injection of lipopolysaccharide. After 24 hours of modeling, serum renal function, renal injury indexes and inflammatory factors were measured, and renal histopathological changes and apoptosis were observed. The levels of Fe²⁺, oxidative stress markers, nuclear factor erythroid 2-related factor 2 (NRF2), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferroportin (FPN), and long-chain acyl-CoA synthetase 4 (ACSL4) in renal tissue were detected. The resluts showed that compared with Mod group, renal tubule necrosis was reduced in Fer-1 group, PNSL group and PNSH group, levels of serum creatinine, urea nitrogen, kidney injury molecule-1, neutrophil gelatinase-associated lipid carrier protein, tumor necrosis factor α, interleukin-1β, and interleukin-6, apoptosis rate, levels of reactive oxygen species, Fe²⁺, content of malondialdehyde, level of ACSL4 protein were lower, while the content of glutathione, superoxide dismutase activity, and the levels of NRF2, GPX4, FPN, and SLC7A11 proteins in renal tissue were higher (all P<0.01). Compared with PNSH group, renal tubule necrosis was more severe in PNSH+ML385 group, and the levels of the above quantitative indexes showed an opposite trend (all P<0.01). In conclusion, PNS may inhibit ferroptosis and alleviate kidney damage in SA-AKI mice by activating the NRF2-GPX4 pathway.