Centaurea benedicta L., commonly known as “cardo santo,” is used as a tonic, antidepressant, anti-inflammatory, antibacterial, and antiseptic in traditional medicine. This study evaluated the topical anti-inflammatory potential of an extract (ECB) and cnicin (CNI) from C. benedicta leaves in a mouse model. Activity was assessed using the ear edema method with croton oil, phenol, capsaicin, and histamine as phlogistic agents. Myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), nitric oxide (NO), t umor necrosis factor α (TNF-α), interleukin 6 (IL-6), and histopathology were assessed as markers of edema/inflammation. Interaction profiles between CNI and cyclooxygenase-1 and -2, induced nitric oxide synthase, and glucocorticoid receptor were examined with molecular docking. Twenty-four h after induction of inflammation, ECB and CNI treatments decreased the thickness and weight of ears by 39.59%– 94.72%. MPO, NAG, NO, TNF-α, and IL-6 levels were also reduced. Histopathological, treatments reduced edema thickness, leukocytes, and vasodilation. Inflammation induced by phenol and histamine was inhibited by ECB and CNI, and ECB suppressed capsaicin-induced inflammation. CNI interacts with cyclooxygenase-1 and nitric oxide synthase through conventional hydrogen bonds, indicating inhibition of these enzymes. ECB and its compound cnicin reduce chemically-induced inflammation in mice suggesting new possibilities for the treatment of diseases associated with dermal inflammatory processes.