Objective: To investigate the renoprotective effects of luteolin on diabetes in rats. Methods: One week after administration of streptozotocin 55 mg/kg intraperitoneally, rats were given 25, 50, and 75 mg/kg/day of luteolin orally for another eight weeks. At the end of the experiment, body weight, blood glucose level, biochemical parameters for renal function (serum creatinine, blood urea nitrogen, uric acid, serum albumin, and total protein), kidney histology, matrix metalloproteinase (MMP)-2, MMP-9, and histone deacetylase 2 (HDAC-2) expression, and malondialdehyde, myeloperoxidase, and hydroxyproline content in renal tissue were evaluated. High glucose-induced damage using NRK-52E cell line was studied to evaluate cell viability and metalloenzyme expression. Additionally, in silico studies including docking and molecular dynamics simulations were conducted. Results: MMP-2, MMP-9, and HDAC-2 expressions were significantly increased in high glucose-induced NRK-52E cells and the renal tissue of diabetic rats. However, these changes were reversed by luteolin at the administered doses. Additionally, luteolin significantly reduced oxidative stress, inflammation, and fibrosis, as well as improved biochemical parameters in diabetic rats. Furthermore, luteolin at the examined doses markedly alleviated diabetes-induced histopathological changes in renal tissues. Conclusions: Luteolin effectively attenuates streptozotocin-induced diabetic nephropathy in rats by inhibiting MMP-2, MMP- 9, and HDAC-2 expression, and reducing oxidative stress and inflammation.