This review explores the role of mitochondrial dysfunction, oxidative stress, and inter-organ miscommunications in the progression of type 2 diabetes (T2D). It highlights that T2D development is not solely driven by peripheral insulin resistance (IR) but also by early β-cell dysfunction, which may occur without significant IR. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is a key factor in T2D onset and progression. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress leads to inter-tissue miscommunication, mediated by extracellular vesicles (EVs), including those containing mitochondria. Under metabolic stress, EV-mediated communication between β-cells and skeletal muscle can trigger mitochondrial anomalies, leading to prediabetes and T2D. The review discusses the molecular mechanisms of ROS-related pathogenesis in prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. It also explores therapeutic avenues for attenuating oxidative damage, reversing prediabetes, and preventing T2D progression. The review emphasizes the importance of understanding the role of ROS in glucose metabolism, insulin secretion, and skeletal muscle function. It also discusses the impact of mitochondrial dysfunction on β-cell function and the role of mitophagy in maintaining β-cell health. The review highlights the importance of inter-organ communication in T2D, with a focus on the role of EVs and mitochondria-containing EVs in promoting inter-tissue miscommunication during prediabetes and T2D. The review concludes that understanding the mechanisms of oxidative stress and mitochondrial dysfunction is crucial for developing novel therapeutic strategies to prevent and treat T2D.This review explores the role of mitochondrial dysfunction, oxidative stress, and inter-organ miscommunications in the progression of type 2 diabetes (T2D). It highlights that T2D development is not solely driven by peripheral insulin resistance (IR) but also by early β-cell dysfunction, which may occur without significant IR. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is a key factor in T2D onset and progression. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress leads to inter-tissue miscommunication, mediated by extracellular vesicles (EVs), including those containing mitochondria. Under metabolic stress, EV-mediated communication between β-cells and skeletal muscle can trigger mitochondrial anomalies, leading to prediabetes and T2D. The review discusses the molecular mechanisms of ROS-related pathogenesis in prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. It also explores therapeutic avenues for attenuating oxidative damage, reversing prediabetes, and preventing T2D progression. The review emphasizes the importance of understanding the role of ROS in glucose metabolism, insulin secretion, and skeletal muscle function. It also discusses the impact of mitochondrial dysfunction on β-cell function and the role of mitophagy in maintaining β-cell health. The review highlights the importance of inter-organ communication in T2D, with a focus on the role of EVs and mitochondria-containing EVs in promoting inter-tissue miscommunication during prediabetes and T2D. The review concludes that understanding the mechanisms of oxidative stress and mitochondrial dysfunction is crucial for developing novel therapeutic strategies to prevent and treat T2D.