INTRODUCTION: There is a scarcity of literature exploring fluid-based biomarkers that have the potential to provide deeper insights into the cellular mechanisms underlying cervical spondylotic myelopathy (CSM) symptom presentation and postoperative recovery. This systematic review synthesized the literature on invasive, fluid-based biomarkers and their clinical significance with CSM. MATERIALS AND METHODS: A comprehensive search strategy was developed for concepts of biomarkers and CSM. Retrieved results underwent title, abstract, and full-text screening with inclusion criteria being original research including animal or human subjects affected by CSM/compression myelopathy that investigated the relationship between a fluid-based biomarker and CSM. Risk-of-bias was reported using the OHAT Risk of Bias Rating Tool. RESULTS: The search strategy resulted in 191 unique manuscripts, with 20 meeting the predetermined inclusion/exclusion criteria, included in final analysis. Of these, 15 (75.0%) were human studies, two (10.0%) were animal studies, and three studies (15.0%) included both human and animal subjects. Across human studies, the fluid utilized for biomarker assessment was blood, (N = 8, 44.4%), cerebrospinal fluid (CSF) (N = 9, 50.0%), and both blood and CSF (N = 1, 5.6%). The three most common biomarkers assessed across human studies were NSE (N = 4, 22.2%), S100b (N = 4, 22.2%), and pNF-H (N = 4, 22.2%). Risk of bias due to inadequate comparison groups was present in three human studies (16.7%) and two animal studies (40%). CONCLUSIONS: This comprehensive systematic review identified several associations between blood and CSF-based neural, glial, and inflammatory biomarkers and CSM. However, the vast heterogeneity across studies renders it difficult to draw definitive conclusions. Future research within larger, prospective patient cohorts is needed to fully elucidate the utility these biomarkers may hold in the clinical evaluation of patients with CSM.