Aim: To explore the morphological brain changes among active thyroid-associated ophthalmopathy (TAO) patients, inactive TAO patients and healthy controls and to investigate the neuropathological relationship of TAO using magnetic resonance imaging (MRI) data. Methods: In this observational case-control study, we included 35 inactive TAO patients, 37 active TAO patients and 23 healthy controls. Voxel-based morphometry (VBM) analysis was conducted to evaluate the gray matter volume (GMV) changes among groups, and the correlations between GMV alterations and clinical parameters in active and inactive TAO groups were investigated. Results: Active TAO patients showed significantly increased GMV in the right inferior frontal gyrus, left superior frontal gyrus (SFG), orbital superior frontal gyrus, orbital middle frontal gyrus, precuneus and postcentral gyrus compared with controls and significantly increased GMV in the right middle temporal gyrus, left SFG and precuneus compared with the inactive TAO group. No significant differences were observed between the inactive TAO group and healthy controls. Notably, the receiver operating characteristic (ROC) curve analysis demonstrated altered GMV among groups and significantly (p < 0.001) differentiated active TAO from inactive TAO and healthy controls. In addition, the mean GMV in precuneus and postcentral gyrus were significantly associated with clinical parameters in active TAO. Conclusion: Our findings suggested the localized GMV alterations among groups were associated with the pathophysiology of TAO and served as a potential discriminative pattern to detect clinical phases of TAO at the individual level. The altered brain morphometry may suggest a corresponding process of self-repair and remodeling of the brain structure as the disease progresses in TAO.