Reactive oxygen species (ROS), generated as byproducts of cellular metabolism, can disrupt cellular proteins, lipids, DNA, and the extracellular matrix (ECM) by modifying its structural components and altering cellular signaling pathways. The ECM acts as a substrate for cell adhesion and regulates cellular functions. An imbalance between ROS production and antioxidant defense mechanisms leads to oxidative stress, contributing to ECM degradation and the emergence of multiple diseases such as cardiovascular disorders, cancer, Alzheimer’s disease, fibrosis, muscular atrophy, etc. Excess ROS generation may arise from various internal factors, such as mitochondrial dysfunction, ATP generation pathway, peroxisomes, etc., as well as external factors such as ionizing radiation, ultraviolet radiation, pollution, and tobacco smoking. Enzymatic antioxidants such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), along with non-enzymatic antioxidants like vitamins C and E, serve as protective agents against oxidative damage. However, chronic oxidative stress can cause irreversible cellular damage, leading to tissue dysfunction and disease progression. Recent studies have shown the potential of antioxidant-based therapeutic strategies to restore redox homeostasis and prevent disease onset. In this chapter, we discussed the connection between oxidative stress and ECM-mediated disease conditions, focusing on the role of antioxidants in maintaining redox balance. Understanding these interactions could provide new insights into developing targeted therapeutics for oxidative stress-mediated pathologies.