Nuclear factor erythroid-2 related factor 2 (Nrf2), a nuclear transcription factor, modulates genes responsible for antioxidant responses against toxic and oxidative stress to maintain redox homeostasis and participates in varieties of cellular processes such as metabolism and inflammation during myocardial ischemia and reperfusion injuries (MIRI). The accumulation of reactive oxygen species (ROS) from damaged mitochondria, xanthine oxidase, NADPH oxidases, and inflammation contributes to depraved myocardial ischemia and reperfusion injuries. Considering that Nrf2 played crucial roles in antagonizing oxidative stress, it is reasonable to delve into the up or down-regulated molecular mechanisms of Nrf2 in the progression of MIRI to provide the possibility of new therapeutic medicine targeting Nrf2 in cardiovascular diseases. This review systematically describes the generation of ROS, the regulatory metabolisms of Nrf2 as well as several natural or synthetic compounds activating Nrf2 during MIRI, which might provide novel insights for the anti-oxidative stress and original ideas targeting Nrf2 for the prevention and treatment in cardiovascular diseases.