Background: Nephrolithiasis is a major prevalent health problem of the urinary system worldwide. Apigenin, a plant flavonoid, reported having nephroprotective and antihypertensive properties. Aim: To determine the protective effect of apigenin in experimental ethylene glycol (EG)-induced urolithiasis in uninephrectomized hypertensive animals. Materials and Methods: EG was administration in uninephrectomized rats to induce urolithiasis. Then, the rats were administered with apigenin (5, 10, and 20 mg/kg, p.o.) for 28 days followed by the evaluation of behavioral, biochemical, and histological parameters. Results: Chronic administration of EG induces alterations in the serum and urine parameters (urine output, pH, urine density and dry weight, urea nitrogen, creatinine, uric acid, calcium, sodium, citrate, albumin, glycosaminoglycans, and lactate dehydrogenase), which was significantly inhibited by apigenin treatment. Apigenin treatment attenuated EG-induced elevated cardiac and renal oxido-nitrosative stress. RT-PCR analysis revealed that apigenin inhibited EG-induced modulations in neutrophil gelatinase-associated lipocalin (NGAL), bikunin, kidney injury molecule-1 (KIM-1), inducible nitric oxide synthase (iNOs), endothelial nitric oxide synthase (eNOs), and osteopontin (OPN) mRNA expressions in the kidney. Western blot analysis showed that elevated levels of renal bone morphogenetic protein (BMP)-2/4 proteins were decreased by apigenin treatment. It also significantly inhibited cardiac and renal histological aberrations. Conclusion: Apigenin treatment attenuated EG-induced urolithiasis via the modulation of elevated oxidative stress and altered expressions of KIM-1, NGAL, OPN, bikunin, eNOs, iNOs, BMP-2, and BMP-4 in uninephrectomized hypertensive rats.y