Antioxidant in general called as the defense system and a complex mechanism of chemical reactions that protects all the living organisms in various ways including developing a protective shield against diseases causing pathogens, fighting against the malicious threats in the cells of the body, creating a self-operated mechanism to monitor with the ROS induced stress related diseases and ensuring the diagnosis of oxidative stress induced communicable, non-communicable diseases and chronic illness. Overall, the antioxidant plays a multifunctional role, and these are available as natural and synthetic antioxidants, which varies in their properties and functions. A variety of antioxidants were extracted from the plant species, fruits, seed coatings, vegetables, etc., and naturally occurring antioxidants including vitamins, C, A and E, carotenoids, beta carotene, lutein, zeaxanthin, phytocompounds derived from plants used in the pharmacological sector in developing antioxidant-aided drug systems to cure various diseases, also in the food preservation, cosmetics etc., It acts as free radical terminators and retards the chain initiation mechanism. Similarly, the synthetic antioxidants are manmade and found to have numerous applications in the development of ROS and self-mechanism strategy in the development of diseases and protection system. Synthetic antioxidants include several chemical additives and some of them have also the negative impact on the human immune system because of the adaptability variations. Here in this chapter the role of the natural and the synthetic antioxidants in the disease development, diagnostics, and protection against chronic illness were discussed in detail.