Traumatic brain injury (TBI) is a major health and socioeconomic concern in the United States and across the globe. Experimental models of TBI are used to study the mechanisms underlying cell dysfunction and death that result from injury, the functional deficits that result from injury, and the potential of various therapies to treat injury. This thesis explores the fundamental mechanical damage associated with brain trauma, investigating the effects of mechanical deformation on neurons at the molecular, cellular, tissue, and animal levels. First, a novel hydrogel system was developed to support 3-D neuronal cultures, and the cultures were studied in an in vitro model of neuronal injury. The dependence of cell viability on hydrogel stiffness and extracellular matrix ligand concentration revealed a role for molecular interactions in the cellular response to injury. Subsequently, in a rat model of TBI neuronal plasma membrane damage was observed coincidentally with cell death within the hippocampus;​ however not all permeable cells died, suggesting a complex role for plasma membrane damage in neuronal degeneration. The spatial profile of permeable cells in the hippocampus reveals further heterogeneity of neuronal plasma membrane damage, with populations of cells in certain hippocampal subregions exhibiting an increased vulnerability to plasma membrane damage. These observations support recent finite element model predictions of strains in the brain during injury. Finally a system for measuring locomotor disturbances is used for the first time following brain injury. Continued investigation of how neurons deform and fail mechanically will contribute to the understanding of the pathophysiology of brain injury and may help identify potential therapeutic targets.