Human health deteriorates due to the generation and accumulation of free radicals that induce oxidative stress, damaging proteins, lipids, and nucleic acids; this has become the leading cause of many deadly diseases such as cardiovascular, cancer, neurodegenerative, diabetes, and inflammation. Naturally occurring polyphenols have tremendous therapeutic potential, but their short biological half-life and rapid metabolism limit their use. Recent advancements in polymer science have provided numerous varieties of natural and synthetic polymers. Chitosan is widely used due to its biomimetic properties which include biodegradability, biocompatibility, inherent antimicrobial activity, and antioxidant properties. However, due to low solubility in water and the non-availability of the H-atom donor, the practical use of chitosan as an antioxidant is limited. Therefore, chitosan has been conjugated with polyphenols to overcome the limitations of both chitosan and polyphenol, along with increasing the potential synergistic effects of their combination for therapeutic applications. Though many methods have been evolved to conjugate chitosan with polyphenol through activated ester-modification, enzyme-mediated, and free radical induced are the most widely used strategies. The therapeutic efficiency of chitosan-polyphenol conjugates has been investigated for various disease treatments caused by ROS that have shown favorable outcomes and tremendous results. Hence, the present review focuses on the recent advancement of different strategies of chitosan-polyphenol conjugate formation with their advantages and limitations. Furthermore, the therapeutic applicability of the combinatorial efficiency of chitosan-based conjugates formed using Gallic Acid, Curcumin, Catechin, and Quercetin in human health has been described in detail.