This study examined the anti-inflammatory properties of Ikarisoside A, isolated from Epimedium koreanum (Berberidaceae), in lipopolysaccharide (LPS)-stimulated macrophages. Ikarisoside A inhibited the expression of LPS-stimulated inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 cells and mouse bone marrow-derived macrophages (BMMs) in a concentration-dependent manner. In addition, Ikarisoside A reduced the release of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, Ikarisoside A inhibited the activity of p38 kinase and nuclear factor-κB (NF-κB), which are signaling molecules involved in NO production. NO production was inhibited when the cells were treated with LPS and either SB 203580 (a p38 inhibitor) or Bay 11–7082 (an inhibitory κB kinase 2 inhibitor). These results suggest that Ikarisoside A inhibits the production of NO by inhibiting the activity of p38 MAPK and NF-κB. As a result of these properties, Ikarisoside A has the potential to be used as an effective anti-inflammatory agent.