Atherosclerosis (AS) is a chronic inflammatory disease, and macrophages play a key role in all phases of AS. Recent studies have shown that miR-221 is a biomarker for AS and stroke; however, the role and mechanism of miR-221 in AS are unclear. Herein, we found that miR-221 and NCoR levels were decreased in ox-LDL-treated THP-1-derived macrophages. In contrast, DNMT3b, IL-6, and TNF-alpha expression levels were increased under these conditions. Upregulation of miR-221 or NCoR could partially inhibit ox-LDL-induced IL-6 and TNF-alpha expression. Further studies showed that DNMT3b was a target of miR-221. DNMT3b inhibition also suppressed IL-6 and TNF-alpha expression and increased NCoR expression in the presence of ox-LDL. Moreover, DNMT3b was involved in ox-LDL-induced DNA methylation in the promoter region of NCoR. These findings suggest that miR-221 suppresses ox-LDL-induced inflammatory responses via suppressing DNMT3b-mediated DNA methylation in the promoter region of NCoR. These results provide a rationale for using intracellular miR-211 as a possible antiatherosclerotic target.