Cereal grains can be considered as a package containing different nutritional and nutraceutical components. Their polyphenolic compounds are associated with health-promoting bioactivities. Recent investigations are directed towards achieving a greener extraction of polyphenols, discovery of new bioactive polyphenols, coupled with rapid determination of phenolics and their antioxidant capacity in cereal grains. Phenolamides, conjugates between phenolic acids and biogenic amines, have recently been reported in minor cereal crops. Mechanisms underlying the systemic health-promoting properties of polyphenolic substances from cereals, include antioxidant, anti-inflammatory, anti-diabetic, and anti-obesity properties. Both cellular and in vivo approaches are being employed to better reflect the biological relevance. However, the therapeutic agents examined to date have been limited to pure compounds and extractable polyphenols. The systemic health-promoting properties of cereal-derived polyphenols play a pivotal role in the delivery of their localized protective impacts on various tissues in different parts of the human body. The application of network pharmacology has enabled the exploration new bioactivities of cereal-derived polyphenols. Metabolomic approaches have been employed to gain understanding of the bioaccessibility and bioavailability of diverse phenolic compounds from different cereal-based matrices. The polyphenols that are covalently linked to cell wall components of cereal grains are likely to escape the digestion but still contribute to the maintenance and enhancement of human health status.