Effective intervention for mild cognitive impairment (MCI) is key for preventing dementia. As a neuroprotective agent, butylphthalide has the potential to treat MCI due to Alzheimer disease (AD). However, the pharmacological mechanism of butylphthalide from the brain network perspective is not clear. Therefore, we aimed to investigate the multimodal brain network changes associated with butylphthalide treatment in MCI due to AD.A total of 270 patients with MCI due to AD received either butylphthalide or placebo at a ratio of 1:1 for 1 year. Effective treatment was defined as a decrease in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) > 2.5. Brain networks were constructed using T1-magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. A support vector machine was applied to develop predictive models.Both treatment (drug vs. placebo)-time interactions and efficacy (effective vs. ineffective)-time interactions were detected on some overlapping structural network metrics. Simple effects analyses revealed a significantly increased global efficiency in the structural network under both treatment and effective treatment of butylphthalide. Among the overlapping metrics, an increased degree centrality of left paracentral lobule was significantly related to poorer cognitive improvement. The predictive model based on baseline multimodal network metrics exhibited high accuracy (88.93%) of predicting butylphthalide's efficacy.Butylphthalide may restore abnormal organization in structural networks of patients with MCI due to AD, and baseline network metrics could be predictive markers for therapeutic efficacy of butylphthalide.This study was registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR1800018362, Registration Date: 2018-09-13).© 2025 The Author(s). Psychiatry and Clinical Neurosciences © 2025 Japanese Society of Psychiatry and Neurology.