Epilepsy is a debilitating neurological disorder that directly impacts millions of people and exerts a tremendous economic burden on society at large. While traumatic brain injury (TBI) is a common cause, there remain many open questions regarding its pathological mechanism. The goal of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is to identify epileptogenic biomarkers through a comprehensive project spanning multiple species, modalities, and research institutions; in particular, diffusion magnetic resonance imaging (MRI) is a critical component, as it probes tissue microstructure and structural connectivity. The project includes in vivo imaging of a rodent fluid-percussion model of TBI, and we developed a computational diffusion MRI framework for EpiBioS4Rx which employs advanced techniques for preprocessing, modeling, spatial normalization, region analysis, and tractography to derive imaging metrics at group and individual levels. We describe the system’s design, present characteristic results from a longitudinal cohort, and discuss its role in biomarker discovery and further studies.