Objective To observe the effect of Qingluo Tongbi Compound (QTC) on osteoclast dif- ferentiation-related miRNA expressions in adjuvant induced arthritis (AIA) rats, and to study its mecha- nism for treating rheumatoid arthritis (RA). Methods The synovial fibroblasts and monocytes of peripher- al blood from AIA rats were co-cultured to induce osteoclast-like cells. Differently expressed miRNAs in the late stage osteoclasts differentiation were detected by miRCURY™ Array. Real-time quantitative PCR (RT- PCR) was applied to verify the reliability of miRNA array. QTC drug-containing sera and blank sera were prepared and added to the co-cultured system. The osteoclasts were randomly divided into three groups, the blank group, the blank serum group, and the QTC group. RT-PCR was applied to detect the effect of QTC on related differentially expressed miRNAs. Bioinformatics software was applied to analyze related differentially expressed miRNAs. Results miRNA array results showed that as compared with the monocytes group, there were 211 miRNAs differentially expressed in osteoclast-like cell differentiation, including 88 up-regulated miRNAs and 123 down-regulated miRNAs. Results of RT-PCR were consistent with results of the array. RT-PCR showed that the expression level of miR-140-5p was obviously up-regulated after the intervention of QTC. Results of bioinformatics analyses showed that the target gene of miR-140-5p was sig- nificantly enriched in signaling pathways such as the regulation of actin cytoskeleton, Ras signaling path- ways, cAMP signaling pathways, and Rap1 signaling pathways. Conclusions There were various dysregulated expressions of miRNAs in the anaphase of osteoclast-like cells differentiation. QTC participated the regulation of osteoclast differentiation by effecting the expression of miR-140-5p.