Objective: To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. Methods: Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. Results: Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. Conclusion: Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior–inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.