The balance between pro- and antioxidant molecules has been established as an important driving force in the pathogenesis of cardiovascular disease. Chronic heart failure is associated with oxidative stress in the myocardium and globally. Redox balance in the heart and brain is controlled, in part, by antioxidant proteins regulated by the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which is reduced in the heart failure state. Nrf2 can, in turn, be regulated by a variety of mechanisms including circulating microRNAs (miRNAs) encapsulated in extracellular vesicles (EVs) derived from multiple cell types in the heart. Here, we review the role of the Nrf2 and antioxidant enzyme signaling pathway in mediating redox balance in the myocardium and the brain in the heart failure state. This review focuses on Nrf2 and antioxidant protein regulation in the heart and brain by miRNA-enriched EVs in the setting of heart failure. We discuss EV-mediated intra- and inter-organ communications especially, communication between the heart and brain via an EV pathway that mediates cardiac function and sympatho-excitation in heart failure. Importantly, we speculate how engineered EVs with specific miRNAs or antagomirs may be used in a therapeutic manner in heart failure.