DNA fidelity is constantly endangered by various types of intrinsic damages and extrinsic damages. Cells that are affected by DNA damage employ a specific, intricate, and interconnected network of cellular and molecular events (known as DNA damage response (DDR)) in order to maintain genome stability. More importantly, DDR is employed to pass intact genomes on to the next generation. Polyphenols constitute a large group of plant-based secondary metabolites widely present in foods and beverages with plant origins (e.g., fruits, vegetables, grains, spices, soy, essential oils nuts, tea, and wine). Based on chemical structures, polyphenols are grouped into three major phytochemical classes: phenolic acids, flavonoids and non-flavonoids. In this review, we aim to explain how polyphenolic compounds modulate DDR sensors, transducers and mediators, with discussion of how polyphenols modulate apoptosis in response to DNA damage in various types of cancer.