Background Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Caffeine, as the most widely consumed psychoactive substance, has been suggested to have potential effects on the clinical course and disability levels of MS patients. This study aimed to review the current evidence on the effects of coffee/caffeine in patients with MS. Methods This study followed the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis and PRISMA 2020 statement. Clinical evidence regarding the effects of caffeine/coffee in MS patients was considered. A systematic search was performed in PubMed, Scopus, Web of Science, and Embase in October 2023, and updated via handsearching in March 2024. JBI's critical appraisal tools were utilized to scrutinize the risk of bias. Results Out of 297 screened records, eight studies were eventually found to meet our inclusion criteria. The sample size of the studies varied between 12 and 1372 and the study designs were retrospective cohort, RCT, single-blind crossover trial, single-arm pilot study (each one study), and cross-sectional (four studies). No significant association between the level of disability and coffee/caffeine intake has been reported, although it was reported to be associated with cognitive improvements. Discussion Evidence indicates an association between coffee/caffeine consumption, and improved cognitive outcomes in patients with MS, while there is no considerable relationship with the disease disability. Considering the limitations of the evidence, such as the small number of studies, and great diversity in study designs, the findings of this study should translate to clinical practice with caution.