Rheumatoid arthritis (RA) is one of the chronic systemic autoimmune diseases that cardinally affect the joints. Many people all over the world suffer from the disease. Fibroblast‐like synoviocytes (FLSs) play a significant role in the occurrence and development of RA. The long noncoding RNA maternally expressed gene 3 (MEG3) is an imprinted gene, which participates in various cancers as a tumor suppressor. Previous studies have shown that nucleotide oligomerization domain (NOD)‐like receptors 5 (NLRC5) plays a key role in inflammatory and autoimmune diseases. Nonetheless, we know very little about the biofunctionality of MEG3 during the development of RA. In this paper, we used complete Freund's adjuvant (CFA)‐induced rats as RA animal models. The level of MEG3 significantly reduced in CFA‐induced synovial tissues and FLSs, whereas the NLRC5 levels were increased. Enforced expression of MEG3 may be responsible for the decreased level of NLRC5 and inflammatory cytokine level. The results of methylation‐specific PCR suggested that the MEG3 gene promoter was significantly methylated in CFA‐induced synovial tissues and FLSs. More important, hypermethylation of MEG3 promoter could be inhibited by 5‐aza‐2‐deoxycytidine (5‐azadC; methylation inhibitor). Besides, the expression of NLRC5 significantly decreased followed by 5‐azadc. Furthermore, DNA methyltransferases 1 (DNMT1) increased in CFA‐induced synovial tissues and cells. These results indicated that MEG3 regulates RA by targeting NLRC5 potentially. Maternally expressed gene 3 (MEG3) may be involved in the development of rheumatoid arthritis (RA) by affecting the proliferation of fibroblast‐like synoviocytes (FLSs), whereas nucleotide oligomerization domain (NOD)‐like receptors 5 (NLRC5) promotes proliferation of FLSs in RA. Enforced expression of MEG3 decreased NLRC5 expression. These results further verified that MEG3 regulates RA by targeting NLRC5 potentially.