Abstract: Background and Objective: Calycosin is recognized to exhibit a variety of pharmacological properties. This study investigated the anti-inflammatory effects and mechanisms of calycosin. Materials and Methods: Mice were randomly separated into six groups: Control, carrageenan (Car), calycosin (12.5, 25 and 50 mg kg–1) and indomethacin (10 mg kg–1). All groups were treated orally once per day for a week. One hour after the final treatment, paw edema was induced by using carrageenan in all groups except for the control group. The volumes of the paws were recorded 1, 3 and 5 h after carrageenan treatment and paw histopathological changes were assessed. Myeloperoxidase (MPO) activity and IL-1β and TNF-α levels were analyzed by using ELISA. The expression of p-IκBα in the cytoplasm and NF-κB p65 in the nucleus were quantified using Western blotting. Results: Calycosin (25 and 50 mg kg–1) significantly decreased paw edema and had protective effects on paw histopathological changes caused by carrageenan in mice. Further investigation demonstrated that calycosin (25 and 50 mg kg–1) also decreased MPO activity, IL-1β and TNF-α levels, expression of p-IκBα in the cytoplasm and NF-κB p65 in the nucleus. Conclusion: Collectively, these data indicated that calycosin displayed anti-inflammatory bioactivity through down-regulation of NF-κB activation.