Background Patient-reported outcomes (PROs) are increasingly associated with concurrent and future impairments in persons with multiple sclerosis (pwMS). The structural and pathological relationships with PROs in pwMS have not been elucidated. Methods One hundred and forty-two pwMS and 47 healthy controls (HCs) were scanned using 3T MRI and completed a PRO questionnaire named Lifeware ® that outlines the physical and psychosocial abilities. Beck’s Depression Inventory (BDI) assessed levels of depression. T1- and T2-lesion volume, volumes of the whole brain (WBV), gray matter (GMV), white matter (WMV) and lateral ventricle (LVV) were derived using JIM and SIENAX software. Additional deep GM (DGMV) and nuclei-specific volumes of the thalamus, caudate, globus pallidus, putamen, and hippocampus were calculated using FIRST. Ordinal regression models adjusted for age and depression and mediation analyses were used. Results When compared to HCs, pwMS reported significantly greater limitations in mobility domains, including standing up from low seat (p < 0.001), climbing flight of stairs (p < 0.001), lower limb limitation (p < 0.001), limitations in bladder continence (p = 0.001) and fatigability (p < 0.001). Patient-reported limitations related to lower extremity function were explained by age, BDI, and all DGM nuclei volumes (p < 0.029). No such relationships were seen in the HCs. Fatiguability and the extent of life satisfaction were only related to depression (BDI p < 0.001) and not associated with any MRI-based outcomes. Most relationships between structural pathology and PROs were mediated by BDI scores (p < 0.001). In the pwMS group, there were no significant differences in any MRI-based brain volumes between the levels of reported life satisfaction. Conclusion PRO measures of lower extremity limitations were associated with DGM structures and DGM-specific nuclei. These findings promote the relevance of measuring DGM structures as measures directly related to subjective well-being and walking limitations. Depression is a significant mediator of PROs and in particular of life satisfaction.