Heart failure (HF) and cardiac fibrosis constitute a substantial portion of the global cardiovascular disease (CVD) burden and are significant contributors to morbidity and mortality. Several mechanisms are involved in the pathogenesis of HF and cardiac fibrosis, with many studies recognizing apoptosis as a central player in their progression. Apoptosis is a conserved biological process directly regulated by extrinsic and intrinsic stimuli. Non-coding RNAs (ncRNAs) exert critical regulatory functions in gene expression and apoptosis, and their dysregulation may trigger excessive apoptosis, leading to cardiac fibrosis and HF. The current work is structured in two sections. The first section focuses on the role of ncRNAs dysregulation in cardiomyocyte apoptosis. In the final section, we emphasize that inhibiting pro-apoptotic microRNAs (miRNAs) through diverse therapeutic strategies, such as stem cell-derived exosomes and herbal medicine, may attenuate excessive apoptosis and represent a promising approach for the treatment of cardiac fibrosis and HF.