Self-concept or sense of self is often altered in the context of neurological illness. Yet, these core aspects of subjective experience are poorly understood for people with multiple sclerosis (MS). This systematic review aimed to synthesize the findings of quantitative and qualitative studies investigating self-concept in MS. PsycINFO, MEDLINE (PubMed), CINAHL, Scopus, and Web of Science were last systematically searched in May 2021, with the Mixed Methods Appraisal Tool and Consolidated Criteria for Reporting Qualiatative Research used to appraise the quality of the eligible articles. Articles were included if they measured or explored self-concept in MS populations, were published in English and peer-reviewed. A total of 30 studies (11 quantitative, 19 qualitative) were identified. Quantitative studies were synthesized using a narrative approach, with results suggesting that MS is associated with some degree of self-concept change. Qualitative studies were synthesized using thematic synthesis, with results illustrating a complex process of self-concept change that is catalyzed by MS-related events and characterized by varying degrees of resistance to, or acknowledgement of, such changes. Future prospective longitudinal studies are needed to characterize the nature of self-concept change in MS using validated tools that measure relevant aspects of self-concept for the MS population.