The accurate recognition of multiple sclerosis (MS) lesions is challenged by the high sensitivity and imperfect specificity of MRI. To examine whether longitudinal changes in volume, surface area, 3-dimensional (3D) displacement (i.e. change in lesion position), and 3D deformation (i.e. change in lesion shape) could inform on the origin of supratentorial brain lesions, we prospectively enrolled 23 patients with MS and 11 patients with small vessel disease (SVD) and performed standardized 3-T 3D brain MRI studies. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion morphology and disease state. A total of 248 MS and 157 SVD lesions were studied. Individual MS lesions demonstrated significant decreases in volume < 3.75mm3 (p = 0.04), greater shifts in 3D displacement by 23.4% with increasing duration between MRI time points (p = 0.007), and greater transitions to a more non-spherical shape (p < 0.0001). If 62.2% of lesions within a given MRI study had a calculated theoretical radius > 2.49 based on deviation from a perfect 3D sphere, a 92.7% in-sample and 91.2% out-of-sample accuracy was identified for the diagnosis of MS. Longitudinal 3D shape evolution and displacement characteristics may improve lesion classification, adding to MRI techniques aimed at improving lesion specificity.