Methotrexate (MTX) is the first-line agent for rheumatoid arthritis (RA) treatment although it causes hepatotoxicity leading to poor compliance to therapy. Sesame oil is unique due to its unusually high oxidative stability and anti-inflammatory property that attributed mainly to the presence of α-tocopherol and anti-oxidative sesame lignans. These components give sesame oil extraordinary high oxidative stability and anti-inflammatory property. The present study aimed to investigate the anti-hepatotoxic and therapeutic potential of sesame oil alone or in combined therapy with MTX on RA rat model. Assessment of RA performed by measuring paw volume, rheumatoid factor and anti-cycliccitrullinated peptide antibody. Biomarkers of cartilage degeneration (MMP-3) and synthesis, (IGF-1), inflammatory mediators (TNF-α, IL-6, NO), anti-inflammatory mediators(IL-10) and oxidative stress were estimated. MTX mono-therapy were enhanced hepatotoxicity but concomitant administration with sesame oil was able to ameliorating RA biomarker and led to an increase its effectiveness without hepatotoxicity. Therefore combined therapy of MTX with sesame oil may lead to synergistic anti-arthritic action with fewer side effects of MTX on liver.