Background: Targeted agents Bevacizumab and Sunitinib are associated with an increased risk of cardiovascular complications in colorectal and renal cancer settings, respectively. Objective: To elucidate whether renin-angiotensin system (RAS) antagonists can prevent Bevacizumab and Sunitinib mediated cardiotoxicity in a murine model. Methods: A total of 194 male mice received 0.9% saline, Bevacizumab, or Sunitinib for 4 weeks. Within each arm, daily prophylactic intake of water, Hydralazine, Aliskiren, Perindopril, or Valsartan were administered for the entire study period. Following serial hemodynamic and echocardiographic assessments, the hearts were collected for histological and biochemical analyses. Results: Although Hydralazine effectively lowered blood pressure in Bevacizumab or Sunitinib treated mice, it was not cardioprotective. However, prophylactic administration of RAS antagonists prevented the development of hypertension, improved cardiac function, partially preserved cellular integrity, and attenuated cardiac apoptosis at week 4. Conclusion: In a chronic murine model, RAS antagonists partially prevented Bevacizumab or Sunitinib mediated cardiotoxicity.