Objective To investigate the anti-inflammatory effect of helleborus thibetanus franch on collageninduced arthritis (CIA) model rats and its effect on the OPG/ RANK/ RANKL signaling pathway. Methods Sixty female Wistar rats were divided into normal group, model group, positive drug methotrexate (MTX) group, low dose group, medium dose group, and high dose group. The CIA model was established by injecting bovine type Ⅱ collagen into the tail root of rats using the collagen antibody induction method, and drugs were administered by gavage after the model was successfully established. In the normal group, 10 mL/ (kg·d) saline was administered. In the model group, 10 mL/ (kg·d) saline was administered. In the positive drug group, 2 mg/ (kg·d) MTX was administered three times a week. In low, medium, and high dose group, 0. 25, 0. 5, and 1. 0 g/ (kg·d) were administered, respectively. Continuous gavage treatment was applied for 25 days. Body mass of rats was recorded to observe the degree of foot swelling. The ankle arthritis index score was calculated. Micro-CT was used to observe histopathological changes in the ankle joint bone. Hematoxylin-eosin (HE) staining was performed to observe pathological changes in ankle joint bone tissue and synovial membrane. Changes in the number of osteoclasts were determined by tartaric acid phosphatase (TRAP) staining. PCR was used to measure mRNA levels of osteoprotegerin (OPG), nuclear factor-κB receptor activator (RANK), RANK ligand (RANKL), tumor necrosis factor (TNF)-α, and bone morphogenetic protein 2 (BMP-2). Relative protein expression of OPG, RANK, RANKL, TNF-α, and BMP-2 was measured by Western Blot. helleborus thibetanus franch on rats with rheumatoid arthritis and its potential pharmacological mechanism for osteoarthritic protection. Results Compared with the normal group, CIA rats had a lower body mass (P< 0. 05), increased thickness of the plantar foot (P< 0. 05), narrowing of the joint cavity in the ankle joint, gnawing-like bone destruction, and pathological changes in the synovium, such as inflammatory cell proliferation and abnormal synovial hyperplasia infiltration. Micro-CT showed that, compared with the normal group, model, low and medium-dose groups showed an uneven ankle joint surface with an incomplete shape and gnawing-like bone destruction, and the high-dose group showed no significant changes in all indexes. HE staining revealed that the ankle joint of the model group showed joint cavity narrowing, gnawing-like bone destruction, synovial tissue proliferation, and inflammatory cell infiltration. Pathological changes, such as destruction of bone tissue, synovial tissue hyperplasia, and inflammatory cell infiltration, were found in the ankle joint of rats in the model group. Compared with the model group, bone tissue hyperplasia and inflammatory cell infiltration in the ankle joint of rats in low, medium, and high dose groups were significantly improved. TRAP staining showed that the model group had the largest number of osteoclasts, and the number of TRAP-positive osteoclasts was reduced in low, medium, and high dose groups compared with the normal group. qRT-PCR showed that, compared with the model group, relative mRNA expression of OPG and BMP-2 was increased in low, medium, and high dose groups (P< 0. 05), and relative mRNA expression of RANK, RANKL, and TNF-α was decreased in low, medium, and high dose groups (P< 0. 05). Western Blot showed that, compared with the model group, relative protein expression of OPG and BMP-2 was increased in low, medium, and high dose groups (P< 0. 05), and relative protein expression of RANK, RANKL, and TNF-α was decreased ( P< 0. 05). Conclusions Helleborus thibetanus franch may alleviate the inflammatory response in RA rats through an anti-rheumatoid arthritis mechanism involving the OPG/ RANK/ RANKL signaling pathway.