One of the most common microvascular effects of diabetes mellitus (DM) that may result in end-stage renal failure is diabetic kidney disease (DKD). Current treatments carry a substantial residual risk of disease progression regardless of treatment. By modulating various molecular targets, pentacyclic triterpenoid celastrol has been found to possess curative properties in the treatment of diabetes and other inflammatory diseases. Therefore, the present study investigated whether celastrol has anti-inflammatory, antioxidant, and antifibrotic effects as a natural compound against experimental DKD. Streptozotocin (55 mg/kg) was utilized for inducing DKD in a rat model. Antioxidant enzymes and renal function tests were assessed in serum samples. In kidney homogenate, relative miRNA-192-5p and miRNA-21-5p gene expressions were measured. Furthermore, using real-time PCR to evaluate the gene expressions of nucleus erythroid 2-related factor-2 (Nrf-2), matrix metalloproteinase-2 (MMP-2), proapoptotic caspase-3, antiapoptotic Bcl-2, LC-3, and Beclin-1. Moreover, the transforming growth factor β1 (TGF-β1), LC-3, Bcl-2, caspase-3 and NADPH oxidase 4 (NOX4) renal expressions were assessed semi-quantitatively using immunohistochemistry. Seven weeks of celastrol (1.5 mg/kg/day) treatment significantly ameliorated DKD. Celastrol improves kidney functions. Moreover, celastrol treatment demonstrated potent antioxidant effect. The mechanism of apoptosis resulting from the administration of celastrol included the modulation of Bcl-2 and caspase-3 expression in the kidney. Celasterol administration leads to an increase in LC-3 and Beclin-1 renal expression that resulting in autophagy. Celastrol treatment improved renal fibrosis by decreasing TGF-β1 and MMP-2 renal expression. These antifibrotic effects could be due to their ability to inhibit miRNA-192-5p and miRNA-21-5p expression in renal tissues. Celastrol exerts a renoprotective effect by targeting miRNA-21 and miRNA-192, as well as their downstream pathways, such as autophagy, apoptosis, and fibrosis.