Cardiovascular complications induced by high fat are one of the most challenging health problems presently. Oxidative stress, inflammation and fibrosis are major components included in the pathology of diabetic cardiomyopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported as an essential therapeutic target in various diseases for its induction of anti-oxidant enzymes, and other protective enzymes. Additionally, a number of Nrf2 activators showed strong anti-inflammatory properties. In the study, we calculated the Nrf2-dependent anti-oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol in high fat diet-induced diabetic heart injury. The underlying mechanisms of chrysophanol were explored using H9C2 cells in vitro. For the in vivo experiment, cardiac injury was triggered in wild type (Nrf2^+/+) and Nrf2-knockout (Nrf2^−/−) mice by high fat diet, and chrysophanol was administered after high fat feeding for two weeks. In Nrf2^+/+ mice, but not the Nrf2^−/− animals, chrysophanol ameliorated metabolic disorders, improved cardiac function, reduced pathological changes, attenuated oxidative injury, down-regulated inflammatory response and fibrosis progression through regulating different signaling pathways. Our data indicated that the anti-oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol are regulated by Nrf2 expression. Thus, we supposed that chrysophanol could be used as a safe therapeutic strategy to ameliorate cardiac injury induced by high fat diet.