Multiple sclerosis (MS) is a chronic and progressive disease charachterized by disabilities which adversely affect individuals' quality of life (QOL). In the present study, the effect size of exercise therapy on patients' QOL in both physical and mental dimensions were investigated and the moderator effect of a number of selected theoretical and significant practical variables were assessed. Relevant studies, published before July 2015, were identified by searching PubMed, Scopus, Google scholar, and Persian medical databases including IranMedex, Irandoc, Magiran, Scientific Information Database (SID), and Medlib. Supplementary searches were also performed manually by reviewing the reference lists of the relevant articles. Next, using a randomized controlled trial (RCT) design, English and/or Persian-language articles conducted in Iran and evaluating the effect of exercise therapy on physical and/or mental aspects of QOL of MS patients were pooled. Afterwards, two competent reviewers in the field extracted the required data and rated the quality of the studies. Twenty-one journal articles were identified and reviewed, but only 13 of them contained the as much data as required to serve the purpose of the study. The mean effect size of exercise therapy on mental, physical, and overall QOL of the patients were 1.021 (95%CI 0.712-1.331, P < .001), 1.040 (95%CI 0.730-1.349, P < .001), and 0.846 (95%CI 0.508-1.184, P < .001), respectively. Based on the investigated Iranian studies, there is strong evidence confirming the effect of exercise therapy on QOL of patients with MS; there, however, exists a need for more studies to identify and establish effective exercise programs due to the heterogeneity of the studies conducted in this area.