Rheumatoid arthritis (RA) is a common worldwide public health problem, which causes a chronic, systemic inflammatory disorder of synovial joints. Paeoniflorin (PA) has achieved positive results to some extent for the treatment of RA.This study aimed to reveal the potential druggable targets of PA in an experimental RA model using quantitative proteomics analysis.Thirty Sprague-Dawley rats were randomly divided into a normal group, model group and PA group. PA (1 mg/kg) was used to treat collagen-induced arthritis (CIA) rats for 42 days. We used isobaric tags for relative and absolute quantitation-based quantitative proteomics to analyze the synovial tissue of rats. Ingenuity pathway analysis (IPA) software was applied to process the data. The proteins that were targeted via IPA software were verified by Western blots.We found that PA caused 86 differentially expressed proteins (≥1.2-fold or ≤0.84-fold) compared with the CIA group. Of these varied proteins, 20 significantly changed (<0.05) proteins referred to 41 CIA-relative top pathways after IPA pathway analysis. Thirteen of the PA-regulated pathways were anchored, which intervened in 24 biological functions. Next, network analysis revealed that leukemia inhibitory factor receptor (LIFR) and asporin (ASPN), which participate in two significant networks, contributed the most to the efficacy of PA treatment. Additionally, Western blots confirmed the aforementioned druggable targets of PA for the treatment of RA.The results reveal that PA may treat RA by decreasing two key proteins, LIFR and ASPN. Our research helps to identify potential agents for RA treatment.