Rheumatoid arthritis (RA) is a chronic autoimmune, multifactorial, inflammatory disorder characterized by hyperplasia and infiltration of inflammatory cells at the synovial lining leading to destruction of cartilage and bone tissues. Pinocembrin (PCB) is a natural flavonoid extracted as a pure molecule from honey, propolis, and some plants. In this study, we evaluated the antiarthritic effect of PCB in adjuvant induced arthritis (AIA) mice. Treating the AIA mouse model with PCB reduced the arthritis symptoms/score, including edema size, extent of hind paw redness, abnormal movement, and holding inability. At the pathological level, PCB significantly decreased the joint erosion and percentages of infiltrated inflammatory cells. Biochemically, PCB interacts with the transcription factor, SRY-related HMG-box 4 (Sox4), and then modulates its dysregulated expression and the expression of Sox4/Stat3 signaling molecules in AIA mice. These molecules include tumor necrosis factor-α, nuclear transcription factor kappaB, and cyclooxygenase-2, besides the microRNAs; miR-132, miR-202-5p, and miR-7235, which are dysregulated in adjuvant-induced arthritis model relative to the control mice. The possible PCB interaction with Sox4 transcriptional protein was confirmed through molecular docking where three hydrogen bonds were formed at ARG and LYS residues at a stable binding energy of -4.72. Taken together, our data demonstrate that PCB could serve as a therapeutic drug in treatment of RA.