The toxicity associated with synthetic drugs used for treating various diseases is common. This led to a growing interest in searching and incorporating natural functional core structures such as flavonoid and their derivatives via chemical modifications to overcome the toxicity problems and enhance their biological spectrum. Natural core structures such as flavonoids are accepted due to their safety to the environment and owing to their varieties of biological activities such as anti-Alzheimer, antimicrobial, anticancer, anti-inflammatory, antidiabetics, and antiviral properties. Based on their chemical structure, flavonoids are classified into various classes such as flavone, flavanol, flavanone, isoflavone, and Anthocyanin, etc. The present review focuses on the potential role of the flavonoid ring-containing derivatives, highlighting their ability to prevent and treat non-communicable diseases such as diabetes, Alzheimer's, and cancer. The pharmacological activities of the flavonoid's derivatives are mainly attributed to their antioxidant effects against free radicals, and reactive oxygen species as well as their ability to act as enzymes inhibitors. The review covers the synthetic strategies of flavonoid derivatives, structure activity relationship (SAR), and in silico studies to improve the efficacy of these compounds. The SAR, molecular docking analysis will enable medicinal chemists to search further, develop potent and newer therapeutic agents.