Background: The spinal cord (SC) is highly relevant to disability in multiple sclerosis (MS), but few studies have evaluated longitudinal changes in quantitative spinal cord magnetic resonance imaging (SC-MRI). Objectives: The aim of this study was to characterize the relationships between 5-year changes in SC-MRI with disability in MS. Methods: In total, 75 MS patients underwent 3 T SC-MRI and clinical assessment (expanded disability status scale (EDSS) and MS functional composite (MSFC)) at baseline, 2 and 5 years. SC-cross-sectional area (CSA) and diffusion-tensor indices (fractional anisotropy (FA), mean, perpendicular, parallel diffusivity (MD, λ_⊥, λ_||) and magnetization transfer ratio (MTR)) were extracted at C3–C4. Mixed-effects regression incorporating subject-specific slopes assessed longitudinal change in SC-MRI measures. Results: SC-CSA and MTR decreased ( p = 0.009, p = 0.03) over 5.1 years. There were moderate correlations between 2- and 5-year subject-specific slopes of SC-MRI indices and follow-up EDSS scores (Pearson’s r with FA = −0.23 ( p < 0.001); MD = 0.31 ( p < 0.001); λ_⊥ = 0.34 ( p < 0.001); λ_|| = −0.12 ( p = 0.05), MTR = −0.37 ( p < 0.001); SC-CSA = −0.47 ( p < 0.001) at 5 years); MSFC showed similar trends. The 2- and 5-year subject-specific slopes were robustly correlated ( r = 0.93–0.97 for FA, λ_⊥, SC-CSA and MTR, all ps < 0.001). Conclusion: In MS, certain quantitative SC-MRI indices change over 5 years, reflecting ongoing tissue changes. Subject-specific trajectories of SC-MRI index change at 2 and 5 years are strongly correlated and highly relevant to follow-up disability. These findings suggest that individual dynamics of change should be accounted for when interpreting longitudinal SC-MRI measures and that measuring short-term change is predictive of long-term clinical disability.