This study aims to determine the relationship between Duffy antigen receptor for chemokines (DARC) and keloid pathogenesis. DARC expression was determined by immunohistochemistry, real-time PCR, and Western blot analysis. Cell proliferation was assessed by CCK-8 assay. Cell migration and invasion abilities were measured by the shift assay. Levels of CC chemokine ligand 2 (CCL2), CXC chemokine ligand 8 (CXCL8), and matrix metalloproteinase 2 (MMP2) were detected by real-time PCR and ELISA. Our results showed that DARC levels were elevated in human keloid fibroblasts. After knocking down DARC, cell proliferation was not altered, whereas the migration and invasion abilities of keloid fibroblasts were significantly elevated. Additionally, the mRNA expression levels of CCL2, CXCL8, and MMP2 were not influenced by DARC knockdown. However, the secretion of CCL2, but not CXCL8 or MMP2, was significantly increased after DARC knockdown. Our results suggest that DARC might inhibit the secretion of CCL2. Moreover, DARC knockdown increases the migration and invasion abilities of keloid fibroblasts.