High-fat diet (HFD)-induced systemic oxidative damage is critical to the pathological process of obesity and is associated with energy metabolism and cognitive disorders. In our previous research, the coumarin derivative Bis 3 was shown to improve neurological disorders as a potent free radical scavenger. In this study, a 12-week high-fat diet model was established, and mice were randomly divided into 3 groups: standard diet, high-fat diet, and high-fat diet with Bis 3 treatment. Our results demonstrated that Bis 3 attenuated body weight gain and inhibited the development of insulin resistance in high-fat diet-fed mice. Bis 3 protected against high fat-induced intestinal barrier integrity damage and lipid content disorder. HFD-induced hepatocyte lipid metabolism disorder and hepatocyte damage were also alleviated by Bis 3. Moreover, the results of cognitive tests indicated that Bis 3 attenuated high fat-induced cerebral dysfunction, such as cognitive disorders. Importantly, Bis 3 simultaneously ameliorated oxidative stress in the digestive and central nervous systems. These findings suggest that Bis 3 protects against systematic oxidative stress in HFD-induced obese mice, balancing insulin resistance, lipid metabolic disorders, and cognitive disorders through its antioxidative effects, indicating that Bis 3, a novel free radical scavenger, might represent a new therapeutic strategy for high fat-induced chronic systemic redox imbalance.