This study evaluated the effects of irbesartan and propranolol on thyroid hormone (TH)-induced cardiac functional and structural remodeling. A rat model of thyrotoxicosis was established by daily intraperitoneal injections of L-thyroxine (T(4), 100 μg/kg) for 4 weeks. Forty Sprague-Dawley rats were randomly divided into four groups (n = 10 each): control group, T(4) group (T(4) alone), T(4) plus irbesartan group (T(4)-Irb, 30 mg/kg), and T(4) plus propranolol group (T(4)-Pro, 0.5mg/mL of drinking water). Cardiac chamber size and functional parameters were measured by echocardiography and cardiomyocyte diameter. Heart rate (HR) and cardiac fibrosis were determined. T(4) alone showed significantly increased HR and cardiomyocyte width (25.0 ± 1.77 vs. 18.8 ± 0.84 μm, P < 0.001) with fibrosis, reduced left ventricle (LV) longitudinal strain (S(long); -16.0 ± 6.27 vs. -22.7 ± 5.19 %, P < 0.001) compared with control. When compared with T(4) alone, T(4)-Irb showed significantly improved LV S(long) (-21.4 ± 1.84 vs. -16.0 ± 6.27 %, P =0.017) and reduced cardiomyocyte width (21.0 ± 1.0 vs. 25.0 ± 1.77 μm, P =0.002) with comparable HR (458.4 ± 24.3 vs. 486.6 ± 30.1 bpm, P = 0.086). However, T(4)-Pro showed significantly reduced HR with improved LV S(long) without alteration of cardiomyocyte width and fibrosis compared with T(4) alone. In conclusion, renin-angiotensin system (RAS) blocking by irbesartan could significantly attenuate TH-induced cardiac structural and functional remodeling. However, HR reduction by propranolol could not alternate structural remodeling, which may implicate the RAS as having an important role in thyrotoxic cardiomyopathy beyond tachycardia.