Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease pathologically characterized by symmetrical synovitis of small joints, and its pathogenesis has not yet been fully elucidated. Recent studies have found that interleukin-22 (IL-22) plays dual roles at different stages of RA and under different cytokine microenvironments, mainly exerting pro-inflammatory and bone destruction-promoting effects, or protective effects under specific conditions. This article systematically reviews the mechanisms of IL-22 in the course of RA, summarizes recent findings on its activation of downstream signaling networks affecting fibroblast-like synoviocytes (FLS) and osteoclasts (OC), and analyzes the molecular basis and clinical translational potential of IL-22 as a key regulator of inflammation and bone destruction, thereby providing a theoretical basis for novel targeted therapies for RA. IL-22 is an inflammatory cytokine that activates the Janus kinase (JAK) /signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), nuclear factor (NF)-κB, and phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) signaling pathways by binding to the IL-22 receptor. It plays dual pro-inflammatory and anti-inflammatory roles in cell proliferation, apoptosis and immune responses. By regulating the generation, differentiation and immune responses of FLS and OC, IL-22 participates in the occurrence and development of RA, leading to synovial inflammation, pannus formation and bone destruction in the joints of patients with RA.