Brahma-related gene 1 (Brg1) is a key gene in inducing the expression of important endogenous antioxidant enzymes, including heme oxygenase-1 (HO-1) which is central to cardioprotection, while cardiac HO-1 expression is reduced in diabetes. It is unknown whether or not cardiac Brg1 expression is reduced in diabetes. We hypothesize that cardiac Brg1 expression is reduced in diabetes which can be restored by antioxidant treatment with N-acetylcysteine (NAC). Control (C) and streptozotocin-induced diabetic (D) rats were treated with NAC in drinking water or placebo for 4 weeks. Plasma and cardiac free15-F2t-isoprostane in diabetic rats were increased, accompanied with increased plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), while cardiac Brg1, p-STAT3 and HO-1 protein expression levels were significantly decreased. Left ventricle weight/body weight ratio was higher, while the peak velocities of early (E) and late (A) flow ratio was lower in diabetic than in C rats. NAC normalized tissue and plasma levels of 15-F2t-isoprostane, significantly increased cardiac Brg1, HO-1 and p-STAT3 protein expression levels and reduced TNF-alpha and IL-6, resulting in improved cardiac function. In conclusion, myocardial Brg1 is reduced in diabetes and enhancement of cardiac Brg1 expression may represent a novel mechanism whereby NAC confers cardioprotection.