Damage to myocardial tissues, leading to myocardial fibrosis, is a significant pathological hallmark across various heart diseases. SMAD3, a central transcriptional regulator within the transforming growth factor-beta (TGF-β) signaling pathway, plays a pivotal role in the pathological progression of myocardial fibrosis and cardiac remodeling. It intricately regulates physiological and pathological processes encompassing cell proliferation, differentiation, tissue repair, and fibrosis. Notably, SMAD3 exerts crucial influences in myocardial fibrosis subsequent to myocardial infarction, pressure overload-induced myocardial fibrosis, diabetic cardiomyopathy (DCM), aging-associated cardiac fibrosis and myocarditis-related myocardial fibrosis. The targeted modulation of genes or the utilization of compounds, including traditional Chinese medicine (paeoniflorin, baicalin, and genistein et al.) and other pharmaceutical agents that modulate SMAD3, may offer avenues for restraining the pathological cascade of myocardial fibrosis. Consequently, targeted regulation of SMAD3 associated with myocardial fibrosis may herald novel therapeutic paradigms for ameliorating myocardial diseases.