The morbidity and mortality of cardiovascular diseases are increasing globally. Pathological cardiac remodeling plays an important role in the development of cardiovascular diseases. More and more investigations focus on the alterations of cardiac metabolism in pathological cardiac remodeling. Cardiac substrate metabolism is severely impaired during cardiac hypertrophy and heart failure, a shift from fatty acid metabolism to glucose metabolism, resulting in aggravated cardiac dysfunction. This review analyzes the relationship among the metabolism of different substrates in pathological cardiac remodeling. Based on these metabolic changes, we summarize the pharmacological agents, and raise new drug development strategies from the perspective of metabolic regulation, leading to an improved prognosis and treatment of patients with cardiac remodeling diseases.