OBJECTIVE Delays in diagnosis are common in degenerative cervical myelopathy (DCM), and there is a need for additional objective assessments of spinal cord structure and function. The objective of this study was to profile serum protein biomarkers in DCM and determine their potential diagnostic and prognostic utility. METHODS Patients with clinically diagnosed DCM (n = 20) and scheduled to undergo decompressive surgery were prospectively enrolled from July 2022 to August 2023. Serum neuronal and inflammatory proteins in the patients were quantified before surgery and 3 months after surgery. Serum protein levels were compared between the DCM patients and healthy controls (n = 10). Serum biomarkers were also related to pre- and postsurgical functional measures. RESULTS DCM patients had a median age of 70 years, and healthy controls had a median age of 65 years. Presurgical neurofilament light chain (NfL; 30.2 vs 11.2 pg/ml, p = 0.01) and interleukin (IL)–6 (2.9 vs 1.2, p = 0.003) were significantly higher in DCM patients than in controls. Presurgical NfL, IL-6, and brain-derived neurotrophic factor (BDNF) best differentiated DCM and controls (p < 0.001). At 3 months after surgery, serum BDNF (p = 0.001), amyloid beta 42 (p = 0.042), and tumor necrosis factor alpha (p = 0.007) were significantly increased compared to presurgical values. Presurgical serum NfL was significantly associated with improvement in pinch strength after surgery (p = 0.03). Inflammatory biomarkers were linked to improvement in the neck pain–related disability and upper limb function. CONCLUSIONS Presurgical serum levels of NfL, IL-6, and BDNF show potential as diagnostic markers for DCM. Presurgical serum biomarkers of neuronal damage and inflammation predict early postsurgical functional outcomes in DCM.