Despite the devastating global impact of ischemic stroke and traumatic brain injury (TBI), there are few Food and Drug Administration approved treatments. This can be largely attributed to the lack of testing in translational models in the preclinical phase. Therefore, further investigation of stroke and TBI pathophysiology is warranted in a large animal model with similar brain anatomy and physiology to the human brain. Utilizing magnetic resonance imaging (MRI) and high-content histological neuroimaging in a translational porcine model, the current studies aim to identify key cellular and structural changes caused by a permanent middle cerebral artery occlusion that impact stroke recovery and determine how brain functional networks are affected after TBI. The inclusion of stroke lesion location when predicting functional outcomes is likely to improve prognostic ability as there is a direct relationship between brain structures and function. A porcine MRI brain atlas was registered to identify stroke lesion location, and correlations between infarcted brain structures and functional gait data were completed to evaluate the predictive capacity of individual brain structure lesion on neurological outcome. This approach identified neuroanatomical structures involved in motor coordination and function that were prognostic of overall gait outcomes and identified potential targets for therapeutic intervention to facilitate optimal recovery. Functional MRI can be employed to measure network changes after injury and provide early prognosis of functional outcomes, including motor, cognitive, and behavioral deficits. Brain activation maps were evaluated following TBI and compared to healthy control brain networks. Functional connectivity disruptions of brain networks were observed and able to be traced to individual affected anatomical structures. While many of these noninvasive neuroimaging modalities provide spatial and temporal information on tissue composition and brain activity, post-mortem histological assessment can provide deeper quantitative analysis of cell-to-cell interactions following an ischemic stroke. Significant differences in the morphology of microglia/macrophages, astrocytes, neurons, neuronal precursors, and vasculature cells were found in stroked brains compared to healthy controls, designating a stroke cell morphological fingerprint. These neuroimaging techniques can be employed to develop personalized patient recovery, disease progression, rehabilitation, and therapeutic intervention plans.