Background: The impact of yoga on the quality of life and fatigue in patients with multiple sclerosis (MS) has shown various results in different reports. As a result, performing a systematic review and meta-analysis to guide physicians and patients seems necessary. The present study was carried out to evaluate the effect of yoga intervention on the quality of life and fatigue in patients with MS. Method: The present study was designed based on PRISMA guidelines from their inception until October 2019. Two researchers independently performed all steps. We searched several international online databases such as PubMed/Medilne, Scopus, Science Direct, Cochrane Library, PsycINFO, Web of Science, CINAHL, CAM-Quest, CAMbase, IndMED and Google Scholar search engine. The data were analyzed using Comprehensive Meta-analysis Software Ver. 2, while P < 0.05 was considered significant. The protocol of this meta-analysis was registered at PROSPERO with number identifier: CRD42019127168. Results: Overall, 693 patients with MS (yoga (n = 209), exercise (n = 298), control (n = 186) groups) were examined in ten randomized controlled trials (RCTs). According to this meta-analysis, the effect of yoga intervention on fatigue in patients with MS was significantly better compared to the typical MS care group [SMD = -0.872; 95%CI: -1.467 to -0.277, p = 0.004], and did not show significant difference compared to the exercise group [SMD = -0.093; 95%CI: -0.353 to 0.167, p = 0.482]. The effect of yoga intervention on the overall quality of life (compared to the typical MS care group: [SMD = 0.710; 95%CI: -0.172 to 1.592, p = 0.114], and compared to the exercise group: [SMD = -0.453; 95%CI: -0.233 to 1.138, p = 0.195]), physical component (compared to the typical MS care group: [SMD = 0.281; 95%CI: -0.157 to 0.719, p = 0.209], and compared to the exercise group: [SMD = 0.074; 95%CI: -0.125 to 0.273, p = 0.467]), psychological component (compared to the typical MS care group: [SMD = 0.250; 95% CI: - 0.132 to 0.631, p = 0.199], and compared to the exercise group: [SMD = - 0.270; 95%CI: -0.813 to 0.272, p = 0.329]), sexual function (compared to the typical MS care group: [SMD = 0.438; 95%CI: -0.350 to 1.226, p = 0.276]), and cognitive function (compared to the typical MS care group: [SMD = -0.390; 95%CI: -0.008 to 0.789, p = 0.055]) in patients with MS was not significant. Conclusion: Yoga is a simple exercise for patients with MS that is capable of decreasing fatigue in these patients. Keywords: Fatigue; Meta-analysis; Multiple sclerosis; Quality of life; yoga.