Objective: Cognitive deficits, especially those of information processing speed (IPS), are common in multiple sclerosis (MS), however, the underlying neurobiological mechanisms remain poorly understood. In this study, we examined structural and functional brain changes separately, but also in an integrative manner, in relation to IPS performance. Methods: IPS was measured using the symbol digit modalities test (SDMT) in 330 MS patients and 96 controls. Patients with IPS impairment (IPS-I, z-score < −1.5) were compared to patients with preserved IPS performance (IPS-P) on volumetric measures, white matter integrity loss (using diffusion tensor imaging) and the severity of functional connectivity changes (using resting-state fMRI). Significant predictors of IPS performance were used to create groups of mild or severe structural and/or functional damage to determine the relative effect of structural and/or functional changes on IPS. Results: IPS-I patients, compared to IPS-P patients, showed lower deep gray matter volume and less WM integrity, but stronger increases in functional connectivity. Patients with predominantly structural damage had worse IPS (z-score = −1.49) than patients with predominantly functional changes (z-score = −0.84), although both structural and functional measures remained significant in a regression model. Patients with severe structural and functional changes had worst IPS (z-score = −1.95). Conclusion: The level of structural damage explains IPS performance better than functional changes. After integrating functional and structural changes, however, we were able to detect more subtle and stepwise decline in IPS. In subgroups with a similar degree of structural damage, more severe functional changes resulted in worse IPS scores than those with only mild functional changes.