Maternal overnutrition-induced fetal programming predisposes offspring to cardiovascular health issues throughout life. Understanding how these adverse cardiovascular effects are regulated at the maternal–fetal crosstalk will provide insight into the mechanisms of these cardiovascular diseases, which will help in further identifying potential targets for intervention. Here, we uncover a role of oxidative stress caused by prenatal overnutrition in governing cardiac damage. Mice exposed to maternal obesity showed remarkable pathological cardiomyocyte hypertrophy (pmale < 0.001, Cohen’s dmale = 1.77; pfemale < 0.001, Cohen’s dfemale = 1.94), increased collagen content (pmale < 0.001, Cohen’s dmale = 2.13; pfemale < 0.001, Cohen’s dfemale = 2.71), and increased levels of transforming growth factor β (TGF-β) (pmale < 0.001, Cohen’s dmale = 3.02; pfemale < 0.001, Cohen’s dfemale = 4.52), as well as left ventricular dysfunction in adulthood. To cope with increased oxidative stress in the myocardial tissue of offspring from obese mothers, we sought to decrease the effect of oxidative stress and prevent the development of these cardiovascular conditions with use of the antioxidant N-acetylcysteine during pregnancy. As predicted, after treatment with the antioxidant, there was greatly mitigated cardiomyocyte hypertrophy (pmale < 0.001, Cohen’s dmale = 1.31; pfemale < 0.001, Cohen’s dfemale = 0.82) and cardiac fibrosis, including decreased composition of collagen fibers (pmale < 0.01, Cohen’s dmale = 1.45; pfemale < 0.05, Cohen’s dfemale = 1.23) and reduced levels of TGF-β (pmale < 0.05, Cohen’s dmale = 1.83; pfemale < 0.01, Cohen’s dfemale = 3.81). We also observed improved left ventricle contractile function together with the alleviation of enhanced oxidative stress in the myocardial tissue of offspring. Collectively, these results established a crucial role of oxidative stress in prenatal overnutrition-associated ventricular remodeling and cardiac dysfunction. Our findings provided an important target for intervention of cardiovascular disease in overnutrition-related fetal programming.