Oxidative stress, a condition characterized by an excess of harmful reactive oxygen and nitrogen species overwhelming the body's protective antioxidant defenses, is a key factor in the development of many chronic diseases. Endogenous sources, primarily mitochondrial electron transport, are key contributors to reactive oxygen and nitrogen species production, which, when uncontrolled, lead to cellular and molecular damage. Environmental factors, such as toxins and radiation, further exacerbate this imbalance. Chronic oxidative stress impacts vital biomolecules, disrupting cellular function and contributing to aging and various chronic diseases, which include cardiovascular disease (CVD), diabetes mellitus (DM), liver disorders, cancer, and neurodegenerative conditions. In CVD, oxidative stress promotes endothelial dysfunction and plaque formation, while in diabetes, it impairs insulin sensitivity and pancreatic β-cell function, aggravating hyperglycemia. Furthermore, excessive ROS in liver cells trigger inflammation, fibrosis, and increased risk of hepatocellular carcinoma, while neurodegenerative diseases and age-related dysfunctions are similarly driven by progressive oxidative damage. This chapter offers a comprehensive overview of oxidative stress mechanisms underlying these diseases, exploring therapeutic interventions aimed at reducing ROS, enhancing antioxidant defenses, and addressing the challenges and future directions of research.