BACKGROUND: Fatigue, a common and serious symptom in multiple sclerosis patients, negatively affects patients' activities of daily living and their quality of life. While foot reflexology has been widely used in fatigue management in recent years, its effect on multiple sclerosis-related fatigue patients remains unclear. PRIMARY STUDY OBJECTIVE: This systematic review aimed to examine the effect of foot reflexology on multiple sclerosis-associated fatigue. METHODS/DESIGN: The protocol of the systematic review and the article writing were based on Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols criteria. In this systematic review, the literature search was conducted in September 2022, in the databases "Scopus, Web of Science, PubMed, and Cochrane Library," without any year limitation. Inclusion and exclusion criteria were established according to the PICOS criteria. Two independent researchers selected the studies and assessed their quality. The reviewed articles were analyzed using the data extraction form developed by the researchers. SETTING: Systematic review. RESULTS: Seven studies, including six randomized controlled trials and one quasi-experimental study with a total of 434 participants, were included in this systematic review. In six studies, it was found that foot reflexology significantly reduced multiple sclerosis-associated fatigue, while in one study there was a decrease in fatigue level, but the difference was insignificant. CONCLUSION: The reviewed studies showed that foot reflexology positively impacts the management of multiple sclerosis-related fatigue. It is suggested to perform further studies on foot reflexology's usefulness in multiple sclerosis patients, utilizing blinding and randomization techniques, with larger sample sizes and excellent methodological quality.