Orexins are peptides found in the hypothalamus and other peripheral tissues including adipose tissue, the endocrine cells of the gut, adrenal gland testis, and the pancreas. They play important roles in neuro-protection by inhibiting oxidative stress and inflammatory response via their type 1 and 2 receptors (OX1R and OX2R). The expressions of OX1R and OX2R were detected and the physiological function of orexin A in fibroblast-like synoviocytes (FLSs) was investigated in this study. Only OX1R was found on FLSs and the expression of OX1R was decreased in fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLSs) and tumor necrosis factor-α (TNF-α)-treated FLSs. Orexin A exhibited an anti-inflammatory effect on TNF-α treated FLSs. Particularly, orexin A treatment reduced the secretions of interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) as well as the production of reactive oxygen species (ROS). Importantly, we showed that orexin A ameliorated the expression of matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13). Mechanistically, we found that orexin A inhibited TNF-α-induced activation of the nuclear factor-κB (NF-κB) signaling pathway. The current study provides a basis for the potential application of orexin A in the clinical treatment of RA.