Chronic low-grade inflammation contributes to metabolic disorders like obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD). It drives systemic insulin resistance and end-organ complications. Two central mediators of this pathological process are reactive oxygen species (ROS) and eicosanoids, bioactive lipids derived from polyunsaturated fatty acids. ROS and eicosanoids regulate the way in which cells communicate with each other, how the blood vessels function, and how the immune system maintains balance. When the body is overloaded with metabolism, it makes excessive reactive oxygen species (ROS) through mitochondrial dysfunction, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and stress on the endoplasmic reticulum. ROS activate pro-inflammatory pathways like NF-κB, MAPKs, and the NLRP3 inflammasome. It also affects pancreatic β-cell viability, interferes with insulin signaling in skeletal muscle and adipose tissue, and exacerbates vascular dysfunction. Eicosanoids originating from cyclooxygenase and lipoxygenase pathways—such as prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs)—exhibit significant pro-inflammatory effects, exacerbating adipose macrophage infiltration, hepatic steatosis, and endothelial damage. Reactive oxygen species (ROS) and eicosanoids’ interaction makes the inflammatory loop self-sustaining. Oxidative stress increases the production of eicosanoids, and eicosanoids stimulate the production of more ROS. Antioxidants (natural compounds, mitochondria-targeted agents), cyclooxygenases (COX)/lipoxygenases (LOX) inhibitors, and nutritional interventions like omega-3 fatty acids and polyphenols are all therapeutic strategies targeting the axis. Promising preclinical data exist, but the application to clinical practice is complicated by the context-specific functions of reactive oxygen species (ROS) and lipid mediators. The necessity for dependable biomarkers of oxidative-eicosanoid signaling remains. Comprehending and manipulating this interaction can yield innovative strategies to mitigate metabolic inflammation and reduce cardiometabolic risk.