The complicated pathology of current diseases requires an intricate treatment. Today, current application of individual single-target drugs or therapeutic approaches is inadequate to target these diseases not to mentioned perceived shortcomings and presented with numerous adverse effects. The extensive and successful documented findings in natural product researches urges the need to make use of these knowledge in the development of new generation of medicine. Polyphenols are compounds naturally derived from plants and have been describe in many research to have tremendous medical benefit. Therefore, a synergistic combination of readily available drugs or other therapeutic approaches is a favourable approach to enhance efficacy, overcome toxicity and optimize safety. The objective of this review is to describe the synergistic effects between the combination of a variety of polyphenols with synthetic drugs or other therapeutic approaches which can help to improve therapeutic efficacy subsequently minimize the adverse effects of a substance targeted in various diseases focusing mainly on cancer, diabetic, microbial infections and tissue regeneration along with their underlying mechanism.