Cellular inflammation has been recognized as the leading factor in numerous diseases, causing either cell death, organ-specific damage, or genesis of different cancers. Icariin, a flavonol glucoside, extracted from Herba Epimedii, offers various pharmacological activities, including reducing inflammation and an antioxidant effect. We aimed to evaluate the anti-inflammatory mechanisms of icariin focussing on both HO-1/Nrf2 and NF-kB pathways. Acute inflammation was induced in rats via carrageenan in this study. Icariin was injected in a dose of 50 mg/kg. Icariin significantly reduced paw swelling in carrageenan-injected animals. It also ameliorated carrageenan-induced paw histopathological alterations. Icariin significantly increased paw enzymatic and non-enzymatic antioxidants. It decreased paw lipid peroxidation. Icariin decreased paw levels of inflammatory cytokines and NF-kB. The immunohistochemical analysis showed that icariin significantly increased Nrf2 gene expression while decreasing NF-kB and COX-2 gene expression. RT-PCR analysis revealed that icariin injection significantly increased both Nrf2 and HO-1 expression of mRNA. The results of this study collectively show that icariin improved carrageenan-induced paw edema by modulating HO-1/Nrf2 and NF-ĸB signaling.