Grape pomace (GP), a by‐product of wine production, contains bioactive polyphenols with potential health benefits. This study investigates the anti‐inflammatory properties of a polyphenolic fraction derived from GP, obtained by ultrasound‐microwave hybrid extraction and purified using ion‐exchange chromatography. In the inflammation model, mice were divided into six groups: intact, carrageenan, indomethacin, and three GP polyphenols treatment groups. Paw edema was induced by subplantar injection of carrageenan, and the GP polyphenols were administered intraperitoneally at doses of 10, 20, and 40 mg/kg. The anti‐inflammatory effect was evaluated by measuring paw volume, and expression of inflammatory markers: cyclooxygenase‐2 (COX‐2), myeloperoxidase (MPO), and cytokines (IL‐1β and IL‐6), along with lipid peroxidation levels. The GP polyphenols significantly reduced paw edema and expression levels of COX‐2, MPO, and cytokines in a dose‐dependent manner effect, with the highest dose showing the greatest reduction. Additionally, lipid peroxidation levels were also decreased by GP polyphenols treatment at doses of 10 and 20 mg/kg. These findings suggest that ultrasound‐microwave extraction combined with amberlite purification proved to be effective in obtaining a polyphenolic‐rich fraction from GP. Thus, GP polyphenols may serve as a natural anti‐inflammatory and antioxidant agent for treating inflammation and oxidative stress‐related diseases.