Due to its anti-inflammatory and antioxidant capacity and, by inference, its involvement in the myelin stealth attainment, oral nutrient supplementation (ONS) with saffron has recently been investigated as a complementary treatment in multiple sclerosis (MS). The purpose of the present study was to systematically review the literature for randomized controlled trials (RCTs) comparing saffron supplementation to placebo, or other interventions, in patients with an MS diagnosis. PubMed, CENTRAL, and clinicaltrials.gov were searched for relevant completed or ongoing RCTs. The Cochrane’s RoB tool 2.0 was used, and a qualitative synthesis without meta-analysis (SWiM) was performed. In total, five parallel, double-, or triple-blind RCTs were identified, fulfilling the study’s criteria, and were included in the SWiM. Intervention duration ranged from four weeks to a year. The summary RoB revealed some concerns, or even high risk for overall bias. The included RCTs failed to report particularities of their interventions (exact composition, active compound, safety assays, etc.) and adverse events. The SWiM revealed that according to the results of single trials, inflammation markers (TNF-a and IL-17) were reduced, and MS-specific biomarkers (MMP-9 and TIMP-1) and cognition were improved after saffron ONS, although definite conclusions regarding saffron efficacy with regard to these outcomes cannot be drawn. Two RCTs reported improvement in the redox status of patients receiving saffron, whereas, with regard to depression, the findings were conflicting. Overall, ONS with saffron compounds may prove beneficial in improving antioxidant defense and oxidative stress in patients with MS; however, the evidence appears scattered, heterogenous, and inadequate in terms of making any suggestions regarding the direction of effect of other outcomes. Trials of better design and MS-specific outcomes are required.