Myocardial infarction and heart failure represent major global health challenges, leading causes of hospitalization and mortality worldwide, especially among the elderly. Despite considerable advancements in treatment, there remains a substantial need to improve prognostic outcomes through further research into pathogenesis and therapeutic optimization. S100 proteins, as inflammatory factors within the heart, demonstrate binding capabilities to various target proteins. Notably, S100A1, S100A4, S100A8/A9, and S100B have emerged as key players in myocardial infarction and heart failure pathophysiology. This review comprehensively illustrates the underlying roles of these four S100 proteins in myocardial infarction and heart failure, highlights similarities and differences in their mechanisms. By synthesizing recent insights, this review offers valuable references and suggests future research directions to advance our understanding and treatment strategies for myocardial infarction and heart failure. Through continued investigation into S100 proteins, more effective therapeutic targets may be identified, ultimately improving patient care and outcomes in cardiovascular diseases.