The zebrafish is considered one of the most versatile experimental animal models. The transparency of the embryos, the small size, the rapid development and the homology with higher vertebrates have made the zebrafish a valuable model also for drug screening. Its use is closely related for the determination of bioactivity, toxicity and off-target side effects of novel drug candidates, which also allows a thorough evaluation of new targets; thus, it may represent a suitable model for drug screening and the optimization of novel candidates. Flavonoids are polyphenolic compounds widely present in fruits, vegetables and cereals. Polyphenols are important for both plants and humans, considering their involvement in defense mechanisms, particularly against oxidative stress. They protect plants from biotic and abiotic stressors and prevent or treat oxidative-based human diseases. For these reasons, polyphenols are used as nutraceuticals, functional foods and supplements by the pharmaceutical industry. Therefore, the most relevant findings on zebrafish as a useful experimental model to study oxidative stress-linked disorders, focusing on the biological activities of flavonoids, are here summarized and reviewed.