Objective To investigate the effects of isoliquiritigenin ( ISO) on cisplatin-induced acute kidney injury (AKI) in mice and explore the potential mechanism. Methods Thirty C57BL/ 6 male mice were randomly divided into a blank control group, model group, ISO-L and ISO-H groups and a positive control group. A single intraperitoneal injection of cisplatin (20 mg / kg) was applied to establish the AKI model. During the intervention, both blank control group and model group were treated with an equivalent volume of saline, while ISO-L group and ISO-H group were administered by gavage with 7. 5 mg / kg and 30 mg / kg ISO, respectively, while the positive control group was administered by gavage with 20 mg / kg irbesartan. After 3 days, serum was collected to determine the levels of serum creatinine ( SCr) and blood urea nitrogen (BUN). HE and PAS staining were used to detect pathological kidney changes, while immunohistochemical and western blot analyses were used to detect inflammatory cytokines’ ( IL-6 and IL-1β) expression and the activity of Smad3 and NF-κB. Real-time PCR was used to detect changes in inflammatory cytokines and long noncoding Arid2-IR. Results Compared with the model group, ISO intervention significantly reduced the SCr and BUN levels in AKI mice (P< 0. 05), in a concentration-dependent manner. Histopathological staining indicated that ISO intervention significantly reduced the infiltration of inflammatory cells and vacuolar degeneration of renal tubular epithelial cells. Furthermore, it significantly improved renal injury. Additionally, ISO significantly downregulated (P< 0. 05) inflammatory cytokines expression, the activity of Smad3 and NF-κB, and long noncoding Arid2-IR expression, suggesting that ISO inhibited the activation of the Smad3 / Arid2-IR/ NF-κB axis. Conclusions ISO effectively reduced kidney inflammation in AKI mice, possibly through regulation of the Smad3 / Arid2-IR/ NF-κB axis.