The objective of this study was to assess the functional and structural substrates of cognitive network changes in patients with benign multiple sclerosis (BMS), using an analysis of effective connectivity and MR tractography. Using a 3-Tesla scanner, we acquired dual-echo, diffusion tensor (DT) and functional MRI during the performance of the Stroop task from 15 BMS patients and 19 healthy controls. DT MRI tractography was used to calculate DT derived metrics from several white matter (WM) fiber bundles, thought to be involved in cognitive performance. DT MRI metrics from WM fiber bundles not directly related with cognitive performance were also derived. Effective connectivity analysis was performed using statistical parametric mapping. MS patients had significantly abnormal DT MRI metrics in all the structures analyzed. Compared with controls, MS patients had more significant activations of several areas of the cognitive network involved in Stroop performance, bilaterally. Compared with controls, BMS patients also had increased connectivity strengths between several cortical areas of the sensorimotor network and the right (R) inferior frontal gyrus and the R cerebellum, as well as decreased connectivity strengths with the anterior cingulate cortex. Coefficients of altered connectivity were moderately correlated with structural MRI metrics of tissue damage within intra- and inter-hemispheric cognitive-related WM fiber bundles, while no correlations were found with the remaining fiber bundles studied, suggesting that functional cortical changes in patients with BMS might represent an adaptive response driven by damage of specific WM structures.