Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) , a key molecule involved in maintenance of DNA methylation during cell division, is a central epigenetic regulator that orchestrates the suppression of expression of multiple factors that exacerbate RA. We found that murine arthritis tissue and human RA tissue, particularly synovial fibroblasts (SF), exhibit remarkable up-regulation of expression of Uhrf1. SF-specific Uhrf1 conditional knockout mice showed more severe arthritic phenotypes and apoptosis-resistant SF. Integrative analysis of the transcriptome and methylome showed that expression of several cytokines including Ccl20 was up-regulated in Uhrf1-deficient SF. In RA patients, disease activity scores, CCL20 expression, Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, stabilization of UHRF1 by Ryuvidine administration diminished disease pathogenesis in arthritis model mice. Our results demonstrated that UHRF1 expressed in SF can contribute to suppression of multiple pathogenic events associated with RA such as Th17 recruitment, SF apoptosis and bone destruction, suggesting that targeting UHRF1 could represent a novel therapeutic strategy for RA.