Heart failure is the end result of many cardiovascular disorders, including myocardial infarction, hypertension, and diabetes. Regardless of etiology, a key mechanism of heart failure is adverse extracellular matrix (ECM) remodeling. Lysyl oxidase (LOX) is a collagen cross‐linking enzyme that is elevated in failing human hearts, and is associated with cardiac fibrosis. Our goal for this study was to determine if inhibition of LOX in rodents with established cardiac disease would provide protection against further adverse cardiac remodeling and dysfunction. The aortocaval fistula rat surgical model of volume overload (VO) was used. Eight weeks after surgery, both sham‐operated and VO rats were treated with a LOX inhibitor, beta‐aminopropionitrile (BAPN; 100 mg/kg/d). Treatment was administered for six weeks using an osmotic minipump inserted into the peritoneal cavity.Echocardiography was used to assess progressive alterations in cardiac remodeling and function. At 14 weeks, left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, and other indices of cardiac function. Using LV homogenates and fixed sections, interstitial myocardial collagen (immunohistochemistry), and protein expression of collagens I and III (Western Blot) were measured. Collagen cross‐linking was assessed using pyridinoline (Pyd) assay.VO induced significant LV hypertrophy (116% increase vs sham), diastolic LV wall stress (363% increase vs sham), fibrosis (172%, 77% and 22% increase in interstitial myocardial collagen, collagen I and collagen III, respectively, vs sham; p<0.05), and cardiac dysfunction (17% decrease in ejection fraction vs sham). LOX inhibition partially attenuated VO‐induced increases in LV hypertrophy (23% decrease vs VO; p<0.05). Inhibiting LOX also completely attenuated VO‐induced increases in interstitial myocardial collagen, and protein expression of collagens I and III (180%, 76% and 22% decrease, respectively, vs VO; p<0.05). LOX inhibition significantly attenuated increases in cardiac wall stress (33.5% decrease vs VO) and conferred cardioprotective effects as indicated by improved fractional shortening (19% increase vs untreated VO; p<0.05). LOX inhibition also significantly attenuated VO‐induced decreases in contractility, assessed using end systolic pressure‐volume catheterization and preload recruited stroke work (70% and 30% increase, respectively, vs VO; p<0.05). Overall, our data demonstrate the cardioprotective effects of LOX inhibition on the volume overload stressed heart, and its potential to slow or even prevent the transition to heart failure.Support or Funding InformationSupported by the NIH/NCRR #P20RR016456 and the American Heart Association Greater Southeast Affiliate #11GRNT7700002 (jdg).