Oxidative stress has an important role in the pathogenesis of various metabolic disorders in mediating cellular damage and disruption in molecular metabolism. In normal physiological conditions, reactive oxygen species (ROS) helps in regulating metabolic processes, but excessive production of ROS leads to mitochondrial dysfunction and stress to cellular organelles such as endoplasmic reticulum, which eventually interrupts homeostasis and triggers pathological signaling cascades. Furthermore, the activation of NF-κB, MAPKs, PI3K-Akt, and the Keap1-Nrf2-ARE pathway causes inflammation, insulin resistance, and tissue dysfunction. Thus, the thorough understanding of ROS and its effects on metabolic disorders pathogenesis is essential to combat critical molecular pathways. This chapter explores the intricate mechanisms by which ROS influence cellular signaling pathways in metabolic diseases such as diabetes, obesity, and metabolic syndrome and assists in the understanding of interconnection between ROS and antioxidant defense systems, as well as emerging therapeutic strategies targeting ROS-mediated pathways.