Abstract: Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid deterioration in renal function. Naringin, a flavonoid abundant in the Rutaceae family, has been reported to provide protective effects against kidney injury. However, the mechanisms responsible for these effects remain inadequately elucidated. In the present study, the AKI mouse model was established in vivo through a single intraperitoneal injection of 20 mg·kg^-1 of cisplatin, and human kidney-2 (HK-2) cell injury was induced by cisplatin in vitro. Blood urea nitrogen (BUN) and creatinine (CRE) levels were measured using an ELISA kit. Hematoxylin and eosin (H&E) staining, along with periodic acid-Schiff (PAS) staining, were employed to evaluate changes in renal histopathology. Serum concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the mice were assessed using ELISA, and the levels of these cytokines were further analyzed. Morphological alterations in HK-2 cells were examined microscopically. The levels of reactive oxygen species (ROS) in HK-2 cells were quantified using an ELISA kit. The protein expression levels of p-MAPK/MAPK, p-JNK/JNK, p-ERK/ERK, p-NF-κB/NF-κB, p-IκBα/IκBα, IL-6, and TNF-α in renal tissue and HK-2 cells were evaluated through Western blot. The results showed that the serum BUN, Cre, IL-6, and TNF-α levels in the model group mice increased and the renal tissue structure was damaged when compared to the control group, whereas naringin could significantly ameliorate the above pathological changes. Moreover, naringin significantly reduced cisplatin-induced ROS production in HK-2 cells. Western blot results confirmed that naringin notably attenuated the expression of p-MAPK, p-JNK, p-ERK, p-NF-κB, p-IκBα, IL-6, and TNF-α proteins in vitro and in vivo. In conclusion, naringin may ameliorate cisplatin-induced AKI by inhibiting the activation of the MAPK/NF-κB pathway and reducing the production of ROS. All animal experiments were approved by the Institutional Animal Care and Use Committee of Hubei University of Chinese Medicine (approval No: HUCMS202204001).