Background: An estimated 2.3 million individuals affected worldwide are affected by multiple sclerosis. Due to advancements in treatment and earlier diagnosis, there are higher numbers of people living with MS than ever before. There is evidence linking optimal self-management to better outcomes among patients with chronic illnesses; however, regarding adults with MS specifically, the results are inconclusive. The purpose of this study was to determine whether self-management mediates the relationship between facilitators and barriers (comorbidity, condition severity, pain, fatigue, and cognitive deficits) and quality of life.Methods: To complete this cross-sectional correlational quantitative study, the researcher recruited a sample of 196 U.S. adults diagnosed with MS and administered a survey consisting of the Comorbidity Questionnaire for MS, the Patient-Determined Disease Steps, the Numeric Pain Intensity Scale, the Fatigue Severity Scale, the Multiple Sclerosis Neuropsychological Screening Questionnaire, the Multiple Sclerosis Self-Management Scale-Revised, the Multiple Sclerosis International Quality of Life, and a demographic questionnaire. The results were analyzed using multiple linear regression analysis.Results: The studied facilitators and barrier had statistically significant relationship(s) with thedependent variable of QoL; however, the relationship between fatigue, pain, and QoL was notsupported. A relationship exists between comorbidity, condition severity, and symptomatology and self-management. Finally, there is a significant relationship between self-management and QoL; however, self-management did not mediate the relationship between the comorbidity, condition severity, and symptomatology (pain, fatigue, and cognitive deficits) and QoL.Conclusions: By providing an understanding of the factors that hinder or facilitate MS self-management, the findings can inform the development of interventions and the improvement of health outcomes for adults with MS.