Mitochondria participate in essential cellular functions, including energy production, metabolism, redox homeostasis regulation, intracellular Ca2+ handling, apoptosis, and cell fate determination. Disruption of mitochondrial homeostasis under pathological conditions results in mitochondrial reactive oxygen species (ROS) generation and energy insufficiency, which further disturb mitochondrial and cellular homeostasis in a deleterious loop. Mitochondrial redox status has therefore become a potential target for therapy against cardiovascular diseases. In this review, we highlight recent progress in determining the roles of mitochondrial processes in regulating mitochondrial redox status, including mitochondrial dynamics (fusion–fission pathways), mitochondrial cristae remodeling, mitophagy, biogenesis, and mitochondrion–organelle interactions (endoplasmic reticulum–mitochondrion interactions, nucleus–mitochondrion communication, and lipid droplet–mitochondrion interactions). The strategies that activate vagal system include direct vagal activation (electrical vagal stimulation and administration of vagal neurotransmitter acetylcholine) and pharmacological modulation (choline and cholinesterase inhibitors). The vagal system plays an important role in maintaining mitochondrial homeostasis and suppressing mitochondrial oxidative stress by promoting mitochondrial biogenesis and mitophagy, moderating mitochondrial fusion and fission, strengthening mitochondrial cristae stabilization, regulating mitochondrion–organelle interactions, and inhibiting mitochondrial Ca2+ overload. Therefore, enhancement of vagal activity can maintain mitochondrial homeostasis and represents a promising therapeutic strategy for cardiovascular diseases. Display omitted •Vagal system regulates mitochondrial homeostasis in cardiovascular diseases.•Protective effects of vagal system on mitochondrial quality control and redox status.•Roles of vagal system in regulation of multiple mitochondrion-organelle interactions.