Mitochondria, the cell’s powerhouses, generate ATP to sustain essential biological functions. Dysfunctional mitochondria can lead to cell death and subsequent tissue damage. Mitochondrial impairment is a key driver of cellular dysfunction in cardiomyocytes, endothelial cells, and macrophages, contributing to cardiovascular diseases such as atherosclerosis, myocardial ischemia–reperfusion injury, and cardiac hypertrophy. The signal transducer and activator of transcription (STAT) family regulates immune responses, apoptosis, and cell proliferation. Despite evidence suggesting that STATs influence mitochondrial pathways in various cardiovascular conditions, their roles are often contradictory and context-dependent. This review examines the structural and functional dynamics of STATs, their upstream and downstream signaling networks, and therapeutic strategies targeting STAT3 (the most extensively studied isoform), with a particular focus on natural compounds and pharmacological inhibitors. By synthesizing current findings, this review offers valuable insights into STATs as potential therapeutic targets for mitochondrial dysfunction in cardiovascular diseases, while also highlighting directions for future research.