Phenolic compounds are secondary plant metabolites and biosynthesized in plants for environmental adaptation and act as antioxidants against intense sunlight, antifeedants, and antibiotics. Several phenolic compounds have the potential to increase healthy lifespan and are therefore being used as anti-aging drugs. Various phenolics, mainly polyphenols, are applied as supplements in aquafeeds to boost immunity and increase stress tolerance in farmed animals. Optimum curves have been reported for many phenolic supplements, indicating that adverse dietary doses are possible. This means that toxicological evaluation of dietary supplements should be mandatory to avoid false perceptions of safety. In addition, the low-dose range of potentially toxic phenolics is not well documented. Recent studies show that low dietary doses of gossypol may actually be beneficial. On the other hand, high doses of the apparently beneficial quercetin may be harmful. Even fewer studies have examined the epigenetics of dietary phenolics in aquatic animals, although these compounds have long been known for their health and immune-enhancing effects in humans, livestock, and animal models. In human medicine, the various epigenetic pathways induced by dietary polyphenols are beginning to be used as anticancer treatments. It does not take much imagination to predict that epigenetic anticancer effects are not the only beneficial effects induced by dietary phenolics. Furthermore, although there are a large number of studies on the supplementation of dietary polyphenols in aquafeeds, there are very few studies using structure-activity relationships. These techniques, as well as artificial intelligence in the medium term, will help to make dietary supplementation more targeted, i.e., more economical.