Objective The objective of this article is to investigate the neurological substrates associated with medication overuse (MO) in patients with chronic migraine (CM). Methods We recruited age- and sex-matched CM patients with MO (CMwMO), CM patients without MO (CMwoMO), and healthy controls (HCs). Magnetic resonance T1-weighted images were processed by voxel-based morphometry, and the findings were correlated with clinical variables and treatment responses. Results A total of 66 patients with CM (half with MO) and 33 HCs completed the study. Patients with CMwMO compared to the patients with CMwoMO showed gray matter volume (GMV) decrease in the orbitofrontal cortex and left middle occipital gyrus as well as GMV increase in the left temporal pole/parahippocampus. The GMV changes explained 31.1% variance of the analgesics use frequency. The patients who responded to treatment had greater GMV in the orbitofrontal cortex (p = 0.028). Patients with CM (with and without MO), compared with HCs, had decreased GMV at multiple brain areas including the frontal, temporal and occipital lobes, precuneus and cerebellum. Conclusions Our study showed GMV changes in CMwMO patients compared to the CMwoMO patients. These three cerebral regions accounted for significant variance in analgesics use frequency. Moreover, the GMV of the orbitofrontal cortex was predictive of the response to MO treatments.