Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD). Urotensin II ((U-II)) and its receptor (UTR) are involved in the progression of CVD through enhancement in the production of reactive oxygen species (ROS). Since silymarin (SMN) is a natural agent with anti-diabetic effects, this study aimed to investigate the antioxidant potency of SMN on the expression of (U-II)/UTR system and oxidative stress status in the heart of type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into six groups (n = 6). Control and diabetic groups treated with or without SMN (60 and 120 mg/kg/day) for 2 months. Fasting blood sugar (FBS), insulin, lipid profile, creatine kinase-MB ((CK-MB)), lactate dehydrogenase (LDH) and markers of oxidative stress were measured by spectrophotometric methods while (U-II) and UTR gene expression was determined by qPCR method. SMN significantly reduced the FBS level, increased the concentration of insulin and improved HOMA-IR. SMN prevented diabetes-induced weight loss, and attenuated the increased levels of total oxidative status (TOS), malondialdehyde (MDA), and nitric oxide (NO). Diabetes-induced reduction of total thiol molecules content (TTM) was normalized to the normal level in SMN treated rats. SMN significantly modulated serum lipid profile, reduced the expression of (U-II) and UTR in the heart, and improved histopathological changes in the heart tissues. Therefore, the current study indicated that SMN ameliorated unpleasant diabetic characteristics via down-regulation of (U-II) and UTR gene expression and modulation of oxidative stress in the heart tissue of type 2 diabetic rats.