Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, which causes demyelination and neuroaxonal damage. Low-grade systemic inflammation has been suggested to contribute to the pathogenesis due to amplification of pathogenic immune activation. However, there is a lack of reliable biomarkers of systemic inflammation predicting disease activity and progression in MS. The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) have been identified as biomarkers of severity and disease activity in various disorders. In September 2020, we conducted a systematic literature search on multiple databases on studies reporting NLR values or CRP levels in MS. The aim of this systematic review was to highlight the current knowledge about the potential of NLR and CRP as biomarkers in MS. A total of nineteen articles qualified for inclusion. Data on CRP were included in fourteen studies and NLR in nine studies. The results regarding CRP were inconsistent, and present literature does not support the use of CRP as a diagnostic or prognostic biomarker in MS. In contrast, NLR values were increased in MS patients compared with healthy controls in all case–control studies. Furthermore, NLR was associated with disease activity in untreated patients. Our systematic review therefore indicates that NLR might serve as a potential biomarker of disease activity. Given that the results of NLR are mainly drawn from retrospective case–control or cross-sectional studies, future prospective studies with long-term follow-up are required to accurately determine optimal timing and cutoff values that may be used in the clinical setting.