Cucumis callosus dry fruits are traditionally used as folk remedy to treat conditions like urethral irritations, urine stoppage or dribbling and other urinary ailments of man in north-west India. But no study is reported to validate this ethnic practice of using Cucumis fruit in urolithiasis. To evaluate anti-urolithiatic potential of Cucumis, hyperoxaluria was induced in rats by supplying 0.75% ethylene glycol (EG) + 1% ammonium chloride (AC) in drinking water for 14 days. Anti-urolithiatic activity of Cucumis callosus hydro-ethanolic extract (CCHEE) was assessed by measuring blood and urine biochemical parameters, oxidative stress indices, histopathology and osteopontin (OPN) expression. Administration of EG-AC to rats caused hyperoxaluria, crystalluria, azotaemia, oxidant/antioxidant imbalance (increase in lipid peroxidation (LPO), and decrease in glutathione (GSH) and catalase (CAT)), up-regulation of OPN and calcium oxalate (CaOx) crystal deposition in kidney. Treatment of afflicted rats with Cucumis fruits extract restored renal function to a great extent (CCHEE group), testified by improvement of stated parameters. Findings demonstrate curative efficacy of Cucumis fruit extract in EG induced urolithiasis of rats. The restoration of renal function was possibly by regulating renal stone formation via reducing urinary oxalate excretion, correcting oxidant/antioxidant imbalances, and reduced expression of OPN. Hence, results of this study validate the ethnic practice of using Cucumis fruit and conclude that fruit extracts have beneficial effects on CaOx urolithiasis and renal function.