Through pattern recognition receptors, infections and tissue injuries drive innate immune cells to trigger inflammation with elevated cytokines, chemokines, growth factors, and other mediators. Inflammation resolves upon removal of pathogenic signals and the presence of pro-resolving conditions including combating adaptive immunity. Failure of resolution progresses into chronic inflammation, manifesting as detrimental disease development known as inflammatory diseases including cardiovascular diseases, diabetes, obesity, cancers, etc. Inflammation typically involves activations of many intracellular signaling pathways such as PI3K/AkT/mTORC1, PI3K/AkT/IKK(JNK), Ras/Raf/MEK/ERK, JAK/STAT, etc.; these pathways could in turn mediate the upregulations of proinflammatory transcription factors (e.g., NFκB, activator protein 1 (AP-1), HIF, signal transducer and activator of transcription (STAT), etc.). Furthermore, the resulting FOXO inactivation ensures inflammatory proceeding. This review provides a systematic view that polyphenols target multiple inflammatory components and reinforce anti-inflammatory mechanisms by antioxidant potentials, AMPK activation, PI3K/AkT inhibition, IKK/JNK inhibition, mTORC1 inhibition, JAK/STAT inhibition, TLR suppression, and ACE inhibition. As a result, polyphenols readily lead to NFκB, AP-1, HIF, and STAT inactivations with reduced proinflammatory mediator generation. In conclusion, polyphenols sustain resolution of inflammation and antagonize against proinflammation, which is readily consistent with diverse anti-inflammatory actions. The promoted, restored, and maintained tissue homeostasis beyond its anti-inflammatory effects also extends to diverse health benefits for disease preventions and interventions.