Euryops arabicus (Astraceae) is grown in Arab Peninsula. Its areal parts possess ethnomedicinal applications against several inflammatory conditions.To evaluate the anti-inflammatory activity of Euryops arabicus (E. arabicus) organic extract as well as its major polymethoxylated flavonoids.Acute toxicity of the total extract of Euryops arabicus (E. ararbicus) was evaluated by assessing LD. In vivo anti-inflammatory activity was evaluated in rats injected with carrageenan in the plantar area. Paw edema volume, histological changes and rats'stair climbing and motility were assessed. In vitro anti-inflammatory activity of the isolated compounds was evaluated in peripheral blood mononuclear cells (PBMCs) challenged with carrageenan. Inflammation markers were assessed in cellular lysates and collected media.The extract was found safe and considered unclassified with an oral LD50 > 2000 mg/kg in rats. Pretreatment of rats with a total extract of E. arabicus at doses of 100 and 250 mg/kg significantly inhibited carrageenan-induced increase in paw edema volume and histopathological changes. Also, it significantly ameliorated diminution of climbing and motility. Phytochemical studies led to the isolation and identification of five polymethoxylated flavonoids. The anti-inflammatory properties of the isolated compounds were evaluated in carrageenan-challenged peripheral blood mononuclear cells (PBMCs). All compounds exhibited appreciable antioxidant activities. Further, pre-incubation of the cells with the isolated metabolites significantly ameliorated the rise in cyclo-oxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) induced by carrageenan challenge. Further, the compounds inhibited the leakage of interleukin-1β (IL-1β), interleukin-6 (IL-6) and myeloperoxidase (MPO) in media collected from stimulated cells.E. arabicus exhibited in vivo anti-inflammatory effects in the carrageenan model as it ameliorated rat paw edema, histopathological changes and movement dysfunction. In vitro activity of isolated compounds was confirmed in stimulated PBMCs. Thus, the anti-inflammatory activity of E. arabicus can be attributed, at least partly, due to its anti-oxidant, anti-inflammatory and anti-chemotactic properties.