Background The chronic inflammatory autoimmune illness of rheumatoid arthritis (RA) is defined by continuous symmetrical joint inflammation and joint distortions, as well as by bone loss which leads to a serious handicap. Calprotectin is a heterodimer formed by two proteins (S100A8 and S100A9) released from leukocytes, macrophages, and monocytes, with an important role in the process of several inflammatory diseases including RA. Aim The present research seeks to study the discriminatory capacity of calprotectin to distinguish between clinically active and inactive disease in RA patients despite the recently used laboratory examinations being normal. Patients and methods This study included 60 patients (25 patients diagnosed as active RA with low C-reactive protein (CRP); 15 patients diagnosed as active RA with high CRP; 20 patients with inactive RA (remission); and 20 apparently healthy volunteers as the control group. Results When RA patients were compared with healthy controls, serum calprotectin levels were significantly higher. Serum calprotectin levels were also shown to have statistically significant relationships with Disease Activity Score 28 score, erythrocyte sedimentation rate, and anti-cyclic citrullinated peptide. Serum calprotectin showed an 88% sensitivity and 90% specificity for detecting RA activity at a threshold level of more than 6 ng/dl. Conclusion Calprotectin plays an essential role in evaluating illness activity in RA patients, with added usefulness in assessing RA’s inflammatory activity, particularly in individuals who do not have high levels of conventional acute-phase reactants like interleukin-6 (erythrocyte sedimentation rate, CRP).