This study aims to explore the association between brain structural connectivity and 1-year demoralization in patients with newly diagnosed breast cancer. Patients were enrolled from a multicenter longitudinal program named as (BRBC) between 2017 and 2019. Brain structural connectivity was assessed with diffusion tensor imaging (DTI) at baseline and the demoralization scale II collected self-report data at baseline and 1 year later. A data-driven correlational tractography was performed to recognize significant neural pathways associated with the group membership (increased vs. nonincreased demoralization). The incremental prediction values of Quantitative Anisotropy (QA) extracted from the significant white matter tracts against the group membership were evaluated. 21.2% ( = 31) reported increased 1-year demoralization. Inferior fronto-occipital fasciculus (IFOF) was associated with 1-year demoralization in breast cancer. The incremental prediction values of QAs in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) ranged from 8.11% to 46.89% and 9.12% to 23.95%, respectively, over the conventional tumor-nodal metatasis (TNM) staging model. Anisotropy in IFOF is a potential prediction neuromarker to 1-year demoralization in patients with newly diagnosed breast cancer. ClinicalTrials.gov identifier: NCT03026374.