Caffeic acid (CA) is a phenolic acid widely found in fruits and plants, which exhibits anti-oxidative, anti-inflammatory, anti-tumor and immunomodulatory properties. Because increased level of reactive oxygen species (ROS) is related to the pathogenesis of rheumatoid arthritis (RA), we treated RA-derived fibroblast-like synoviocytes (RA-FLS) with CA, and investigated its effects on cytokine production, expression levels of prostaglandin E2 (PGE2) and matrix metalloproteinases (MMP)-1. Our results showed that high level of CA induced cell apoptosis in RA-FLS. CA significantly reduced productions of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) in FLS. Moreover, PGE2 and MMP-1, which play vital roles in RA development, were significantly repressed by CA at both transcriptional and translational levels. To reveal the underlying mechanisms, we compared the levels of proteins involved in mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways between CA and vehicle treated groups, and found that CA exerted its regulatory function on cytokine production via inhibiting phosphorylation of NF-κB inhibitor kinase (IκB kinase/IKK) α/β and IκBα. In conclusion, this study has, for the first time, demonstrated the effects of CA on repressing IL-6 and TNF-α to alleviate inflammation response in RA-FLS by blocking phosphorylation of IκB and IκB kinase. Clinical use of CA may be effective in RA treatment.