<b><i>Introduction:</i></b> Cardiac aging is the major risk factor for advanced heart disease, which is the leading cause of death in developed countries, accounting for &#x3e;30% of deaths worldwide. <b><i>Objective:</i></b> To discover the detailed mechanism of cardiac aging and develop an effective therapeutic candidate drug to treat or delay cardiac aging. <b><i>Methods:</i></b> We used D-galactose to induce cardiac aging in Nrf2^+/+ and Nrf2^–/– mice, and then treated these mice with vehicle or the Nrf2 activator, CDDO-imidazolide (CDDO-Im). <b><i>Results and Conclusions:</i></b> D-galactose injection significantly induced cardiac aging, cell apoptosis, and oxidative stress in Nrf2^+/+ mice, all of which were further exacerbated in Nrf2^–/– mice. CDDO-Im treatment can effectively weaken oxidative stress and enhance the activities of antioxidant enzymes, but CDDO-Im lost its antioxidative effect in the Nrf2^–/– mice. Nrf2 activator CDDO-Im could therefore effectively protect against D-galactose-induced cardiac aging by inhibiting oxidative stress, suggesting that CDDO-Im might be a potential and promising therapeutic candidate drug to treat cardiac aging.