Background and Objectives: Oxalate is a toxic metabolite, which is predominantly excreted through the kidneys. Hyperoxaluria is a clinical condition characterized by the occurrence of excessive amounts of oxalate in the urine. Hyperoxaluria affects most of the patients with kidney stone. In this study, we aimed to reveal the therapeutic actions of escin against the hyperoxaluria-induced nephropathy in rats through the suppression of inflammation and oxidative stress. Materials and Methods: Wistar rats were induced with hyperoxaluria via administration of 0.4% ethylene glycol and 1% ammonium chloride through drinking water and treated with 50 mg/kg of escin for 28 days. The bodyweight, water intake, and urinary output was monitored and tabulated. The renal markers such as urinary kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were examined using assay kits. The pro-inflammatory cytokines such as IL-1 β, IL-6, and monocyte chemoattractant protein-1 (MCP-1) were quantified using kits. The MDA and antioxidant enzymes such as superoxide/dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were investigated using kits. The mRNA expression of CCAAT/enhancer-binding protein homologous protein and GRP78 was studied by reverse transcription–polymerase chain reaction analysis. Results: Escin remarkably improved the bodyweight and decreased the renal weight, water uptake, and urinary output in Wistar rats. The status of urinary oxalate, LDH, NAG, and KIM-1 was appreciably suppressed by the escin treatment. Escin also reduced the levels of interleukin (IL)-1 β, IL-6, MCP-1, and lipid peroxides and increased the activity of antioxidant enzymes such as SOD, GPx, and GR. It downregulated the expression of CHOP and GRP78. Furthermore, histological examination of escin-treated hyperoxaluric animals revealed improved kidney structures. Conclusion: The results of this study revealed that escin shows potent therapeutic actions against hyperoxaluria-induced nephropathy in rats.