Fraxinellone is formed by the natural degradation of limonoids isolated from the root bark of Dictamnus dasycarpus. Fraxinellone has been reported to possess neuroprotective and vasorelaxing activities, but the effects and the mechanism of fraxinellone in inflammation have not been fully characterized. It was shown, that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Moreover, these results proved that fraxinellone could be use as a novel drug candidate in the treatment of colonic inflammation.