This review provides a comprehensive understanding of how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. Polyphenols regulate immunity by interfering with immune cell regulation, pro-inflammatory cytokine synthesis, and gene expression. They inactivate NF-κB, modulate MAPK and arachidonic acid pathways, inhibit PI3K/Akt, IKK/JNK, and mTORC1, and suppress TLR and pro-inflammatory gene expression. Their antioxidant activity and ability to inhibit enzymes involved in eicosanoid production contribute to their anti-inflammatory properties. Polyphenols inhibit enzymes involved in ROS production and upregulate endogenous antioxidant enzymes. The effects of these compounds on the immune system are associated with extended health benefits for chronic inflammatory diseases, including diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases. The review highlights the immunomodulatory effects of dietary polyphenols, their anti-inflammatory abilities, and their contribution to protecting against chronic inflammatory diseases, with a focus on their anti-cancer activity.This review provides a comprehensive understanding of how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. Polyphenols regulate immunity by interfering with immune cell regulation, pro-inflammatory cytokine synthesis, and gene expression. They inactivate NF-κB, modulate MAPK and arachidonic acid pathways, inhibit PI3K/Akt, IKK/JNK, and mTORC1, and suppress TLR and pro-inflammatory gene expression. Their antioxidant activity and ability to inhibit enzymes involved in eicosanoid production contribute to their anti-inflammatory properties. Polyphenols inhibit enzymes involved in ROS production and upregulate endogenous antioxidant enzymes. The effects of these compounds on the immune system are associated with extended health benefits for chronic inflammatory diseases, including diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases. The review highlights the immunomodulatory effects of dietary polyphenols, their anti-inflammatory abilities, and their contribution to protecting against chronic inflammatory diseases, with a focus on their anti-cancer activity.