Rheumatoid arthritis (RA) is one of the major causes of disability that aggrieve a financial burden for the healthcare system as well as for patients. Both stem cell therapy and low-dose radiotherapy (LD-RT) have been recognized as alternative approaches to alleviate pain, inflammation, and bone in the inflamed joints. Accordingly, the present study was designed to compare the efficacy of both modalities in the treatment of RA in experimental rats. Rheumatoid arthritis was induced in forty female rats using Complete Freund's adjuvant (CFA), divided into four groups (arthritic induction group and three treatment groups) compared to controls: one of the treatment groups received Human's Wharton Jelly Mesenchymal Stem Cells (WJMSC), and the other two groups received individual doses of 0.5 and 1 Gy of Gamma irradiation once a week for six weeks. After six weeks animals were sacrificed and examined for joint histology, paw swelling, mRNA gene expression for TNF-α, IL-1β and IL-6 together with serum anticyclic citrullinated peptide (anti-CCP) and nitric oxide (NO). Results showed that both doses of (0.5 Gy and 1 Gy) and WJMSC individually modulated RA effects by significantly decreasing the measured biochemical and molecular parameters. However, at the histology level it was evident that irradiation has a better pronounced effect compared to WJMSC, which showed aggravated effects on joint erosion. The present study reports that both IR and WJMSC significantly decreased Anti-CCP, which is a specific marker for RA, however, WJMSC might have deliberate effects on the synovitis and arthritis.