Oxidative stress and renin-angiotensin system play an important role in podocyte injury and hence in the development and progression of diabetic nephropathy (DN). To assess the combination of silybin and telmisartan effect in preventing podocyte detachment in streptozotocin-induced diabetic rats. Twenty male Wistar rats were divided into 5 groups, each of 4. The 1st group acts as normal rats. The 2nd group acts as untreated diabetic rats. The 3rd group, 4th group, and 5th group act as treated diabetic rats with silybin at doses 50 mg/kg/day, telmisartan at doses 3 mg/kg/day, and a combination of telmisartan 3 mg/kg/day and silybin 50 mg/kg/day. Urinary levels of podocin, nephrin, albumin, and serum cystatin C levels were measured at the end of the study by ELISA. The level of nephrin, podocin, and albumin urine, as well as serum cystatin C level, were significantly lower in the combination therapy group compared with the positive control group. Compared with the monotherapy group, urinary nephrin, podocin, and albumin levels were significantly lower in the combination therapy group, while serum cystatin C levels were not different. In streptozotocin-induced diabetic rats, the combination of silybin and telmisartan is better than monotherapy in preventing podocyte detachment.