Randomized clinical trials (RCT) and observational studies have highlighted the importance of flavonoid consumption for human health. Several studies have associated a high intake of dietary flavonoids with (a) enhanced metabolic and cardiovascular health, (b) enhanced cognitive and vascular endothelial functions, (c) an improved glycemic response in type 2 diabetes mellitus, and (d) a reduced risk of breast cancer in postmenopausal women. Since flavonoids belong to a broad and diverse family of polyphenolic plant molecules—with more than 6000 compounds interspersed in the human diet—researchers are still uncertain whether the intake of single, individual polyphenols or a large combination of them (i.e., synergistic action) can produce the greatest health benefits for humans. Furthermore, studies have reported a poor bioavailability of flavonoid compounds in humans, which presents a major challenge for determining their optimal dosage, recommended intake, and, consequently, their therapeutic value. Especially because of their scarce bioavailability from foods—along with the overall declining food quality and nutrient density in foods—the role of flavonoid supplementation may become increasingly important for human health. Although research shows that dietary supplements can be a highly useful tool to complement diets that lack sufficient amounts of important nutrients, some caution is warranted regarding possible interactions with prescription and non-prescription drugs, especially when taken concurrently. Herein, we discuss the current scientific basis for using flavonoid supplementation to improve health as well as the limitations related to high intakes of dietary flavonoids.