Background: Hepatic ischemia reperfusion injury (IRI) occurs in clinical settings like hepatic transplantation and resection. Hepatic IRI is mediated by induction of oxidative stress and inflammation. Hepatic IRI results in remote organ injury. Acute kidney injury (AKI) is common and increases mortality and morbidity. Extensive experimentations showed that celastrol (CEL) exhibits curative properties in treatment of oxidative and inflammatory diseases through the modulation of a variety of molecular targets. Objective: The current study pointed to investigate the potential protective effect of CEL against hepatic IRI-induced AKI, and to identify the underlying mechanisms. Materials and methods: CEL (4mg/kg, IP, once) was given to rats. After 1 hour rats liver was subjected to 90 min ischemia followed by 4 hrs reperfusion (90/4 I/R). At the end of surgery kidney tissue and blood were collected to evaluate the AKI. Results: Results revealed that compared to I/R group, CEL protected group showed amelioration in renal injury. This was confirmed by a significant reduction in serum BUN and Cr levels with improved histopathological results. Renal protection afforded by CEL was mediated by activating Nrf2/HO-1 signaling, increasing TAC content and decreasing MDA content. Furthermore, CEL protection significantly reduced the inflammatory markers (NF-κB, NLRP3, CASP1, IL-1β, HSP90 and HSF-1) and neutrophilic infiltration assessed as MPO. Conclusion: The reno-protective effect of CEL might be due to its anti-inflammatory and antioxidant properties mediated by (Nrf2‌/HO-1), (NF-κB/NLRP3) inflammasome, and (HSP90/HSF-1) pathways. Thereby, CEL therapy could be a possible strategy to improve the clinical outcomes of liver surgery.