Background: Physical activity, particularly exercise training, is an evidence-based approach for managing symptoms, restoring function and improving overall wellness in people with multiple sclerosis (MS). Several recent studies have argued for a potential disease modifying effect of exercise in people with MS, and among the potential mediating mechanisms are exercise training effects on both cytokines and adipokines. The objectives of this study were to perform a systematic review of exercise training effects on cytokine and adipokine profiles in persons with MS. Methods: We conducted open-dated searches of PubMed, Cochrane Library, EMBASE and PEDro using the terms 'Multiple sclerosis' or 'MS' AND 'exercise' OR 'training' OR 'physical activity' AND 'cytokine' OR 'inflammatory' OR 'immune' OR 'adipokine'. Included studies were written in English; comprised of humans with MS, and evaluated the effects of regular physical activity or exercise on pro-inflammatory, anti-inflammatory cytokines or adipokines. Two authors independently scanned titles and abstracts, and read the studies included. All studies were rated on the PEDro scale and further classified based on American Academy of Neurology criteria. Results: Twelve studies were included of which 10 studies focused on cytokines, 1 study focused on adipokines, and 1 study included both cytokines and adipokines. The selected studies included 3 Class I studies, 7 Class II studies, and 2 Class IV studies and had average PEDro scores of 6.9 ± 1.6. Studies included endurance (n = 5), resistance (n = 3), combined (n = 3), and vibration (n = 1) training. Overall, there is a general lack of standardization of procedures across studies and inconsistent evidence for the effects of physical activity and exercise on cytokine and adipokine profiles in MS, with a general pattern indicating a lack of effect. Conclusion: Research regarding the effects of exercise training on cytokines and adipokines in MS is in its infancy, but exercise represents an adjuvant therapy in MS, and future studies are essential for clarifying the role of exercise on cytokines and adipokines in MS.