Oxidative stress and inflammation are closely linked pathophysiological processes that coexist in many chronic diseases. Despite their interdependence, antioxidant therapies have often failed to show consistent benefits, leading to the "antioxidant paradox." This review explores the relationship between oxidative stress and inflammation and proposes that the paradox may arise from the failure to target both processes simultaneously or the use of non-selective agents that may exacerbate one while mitigating the other. Oxidative stress is defined as an imbalance between oxidants and antioxidants, with recent evidence highlighting the importance of redox signaling. Free radicals and reactive species, such as ROS, RNS, and RCl, play key roles in both oxidative stress and inflammation. Inflammation involves the release of reactive species by immune cells, which can induce oxidative stress, while oxidative stress can also trigger inflammation through various pathways, including the activation of NF-κB. The interplay between these processes is complex, with both contributing to chronic diseases. The failure of antioxidant trials may be due to the inability to address both inflammation and oxidative stress simultaneously, or the use of agents that disrupt redox balance. The review also discusses the role of NF-κB in regulating inflammatory and oxidative responses, and highlights the importance of targeting both processes in therapeutic strategies. The findings suggest that a comprehensive approach, considering both redox status and inflammatory markers, is necessary for effective treatment of diseases linked to oxidative stress and inflammation.Oxidative stress and inflammation are closely linked pathophysiological processes that coexist in many chronic diseases. Despite their interdependence, antioxidant therapies have often failed to show consistent benefits, leading to the "antioxidant paradox." This review explores the relationship between oxidative stress and inflammation and proposes that the paradox may arise from the failure to target both processes simultaneously or the use of non-selective agents that may exacerbate one while mitigating the other. Oxidative stress is defined as an imbalance between oxidants and antioxidants, with recent evidence highlighting the importance of redox signaling. Free radicals and reactive species, such as ROS, RNS, and RCl, play key roles in both oxidative stress and inflammation. Inflammation involves the release of reactive species by immune cells, which can induce oxidative stress, while oxidative stress can also trigger inflammation through various pathways, including the activation of NF-κB. The interplay between these processes is complex, with both contributing to chronic diseases. The failure of antioxidant trials may be due to the inability to address both inflammation and oxidative stress simultaneously, or the use of agents that disrupt redox balance. The review also discusses the role of NF-κB in regulating inflammatory and oxidative responses, and highlights the importance of targeting both processes in therapeutic strategies. The findings suggest that a comprehensive approach, considering both redox status and inflammatory markers, is necessary for effective treatment of diseases linked to oxidative stress and inflammation.