Prolonged skeletal muscle inactivity (e.g. limb immobilization, bed rest, mechanical ventilation, spinal cord injury, etc.) results in muscle atrophy that manifests into a decreased quality of life and in select patient populations, a higher risk of morbidity and mortality. Thus, understanding the processes that contribute to muscle atrophy during prolonged periods of muscle disuse is an important area of research. In this regard, mitochondrial dysfunction has been directly linked to the muscle wasting that occurs during extended periods of skeletal muscle inactivity. While the concept that mitochondrial dysfunction contributes to disuse muscle atrophy has been contemplated for nearly 50 years, the mechanisms connecting mitochondrial signaling events to skeletal muscle atrophy remained largely unexplained until recently. Indeed, emerging evidence reveals that mitochondrial dysfunction and the associated mitochondrial signaling events are a requirement for several forms of inactivity-induced skeletal muscle atrophy. Specifically, inactivity-induced alterations in skeletal muscle mitochondria phenotype and increased ROS emission, impaired Ca²⁺ handling, and release of mitochondria-specific proteolytic activators are established occurrences that promote fiber atrophy during prolonged periods of muscle inactivity. This review highlights the evidence that directly connects mitochondrial dysfunction and aberrant mitochondrial signaling with skeletal muscle atrophy and discusses the mechanisms linking these interconnected phenomena.