Mitochondria are vital organelles which maintain the generation of energy, metabolic functions, and redox balance of cells. These functions are impaired in mitochondrial disorders and, in most cases, lead to overproduction of reactive oxygen species (ROS). The primary source of ROS is leakage of electrons by the mitochondrial electron transport chain (ETC), and their build-up causes oxidative stress which may damage mitochondrial proteins, lipids, and DNA. In addition to direct cellular damage, ROS also serve as signaling molecules and activate major inflammatory signaling pathways, such as NF-κB and NLRP3 inflammasome, and stimulate the production of pro-inflammatory cytokines and chemokines. These inflammatory reactions are now being seen as part of the pathophysiology of primary mitochondrial diseases, including MELAS, LHON, and Leigh syndrome, in which chronic oxidative and inflammatory stress is seen to worsen the clinical manifestations. In addition, the inflammatory process itself may become a source of increased production of ROS, which leads to a self-accelerating process that increases the rate of mitochondrial dysfunction and tissue damage. This interaction between ROS and inflammation is an important connection in the pathogenesis of mitochondrial pathology. Antioxidants (CoQ10, MitoQ, N-acetylcysteine) and anti-inflammatory drugs (corticosteroids, cytokine inhibitors) have been demonstrated to have inconsistent yet promising effects in reducing the severity of the disease through their effects on these processes. Nevertheless, it is still difficult to have the desired, long-term modulation of ROS and inflammatory pathways without disrupting their physiological functions. A better insight into this two-way connection would facilitate the creation of more specific disease-modifying therapies. This chapter examines the mechanistic relationship between ROS and inflammation in mitochondrial diseases, existing treatment approaches, and future opportunities in interfering with this pathological process.