Purpose of Review <p>This review aims to summarize current knowledge of the intrinsic relationship between exercise, spexin, and cardiovascular diseases associated with obesity and diabetes and provide mechanistic insights into the beneficial effect of exercise on obesity, diabetes and cardiovascular diseases.</p> Recent Findings <p>Emerging evidence indicates that spexin has been shown to be beneficial for diabetes and cardiometabolic health in preclinical models. In obese or diabetic states, circulating levels of spexin are significantly reduced, leading to skeletal muscle, the liver, and cardiac muscle becoming more susceptible to insulin resistance. Conversely, exercise triggers the release of spexin under obese or diabetic states, which may improve insulin resistance and cardiometabolic disorders. The mechanisms underlying the improvement of insulin resistance and cardiovascular disorders due to spexin involve increasing glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, as well as reducing the mitochondrial oxidative stress in cardiac tissues.</p> Summary <p>This review summarizes our recent studies and those of others to highlight the underlying molecular mechanisms of the effects of exercise induced spexin on diabetes and cardiovascular diseases. These insights shed new light on the pathophysiology of diabetes and cardiovascular disease based on preclinical studies and may provide useful clues for developing a combination of spexin and exercise as an effective therapeutic strategy for preventing or treating cardiometabolic disorders of obesity and diabetes.</p>