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<i>Punica granatum</i> L. (Punicaceae) is a popular fruit all over the world. Owning to its enriched polyphenols, <i>P. granatum</i> has been widely used in treating inflammation-related diseases, such as cardiovascular diseases and cancer. Twenty polyphenols, containing nine unreported ones, named punicagranins A–I (<b>1</b>–<b>9</b>), along with eleven known isolates (<b>10</b>–<b>20</b>), were obtained from the peels. Their detailed structures were elucidated based on UV, IR, NMR, MS, optical rotation, ECD analyses and chemical evidence. The potential anti-inflammatory activities of all polyphenols were examined on a lipopolysaccharide (LPS)-induced inflammatory macrophages model, which indicated that enhancing nitric oxide (NO) production in response to inflammation stimulated in RAW 264.7 cells was controlled by compounds <b>1</b>, <b>3</b>, <b>5</b>–<b>8</b>, <b>10</b>, <b>11</b>, <b>14</b> and <b>16</b>–<b>20</b> in a concentration-dependent manner. The investigation of structure–activity relationships for tannins <b>6</b>–<b>8</b> and <b>12</b>–<b>20</b> suggested that HHDP, flavogallonyl and/or gallagyl were key groups for NO production inhibitory activity. Western blotting indicated that compounds <b>6</b>–<b>8</b> could down-regulate the phosphorylation levels of proteins p38 MAPK, IKKα/β, IκBα and NF-κB p65 as well as inhibit the levels of inflammation-related cytokines and mediators, such as IL-6, TNF-α, iNOS and COX-2, at the concentration of 30 μM. In conclusion, polyphenols are proposed to be the potential anti-inflammatory active ingredients in <i>P. granatum</i> peels, and their molecular mechanism is likely related to the regulation of the p38 MAPK and NF-κB signaling pathways.