Updated project metadata. The molecular consequences of traumatic brain injuries or TBI are poorly understood. Here, we simulated TBI using an innovative laboratory apparatus employing a 5.1 kg dummy impact generating a ≤3,300 g-force acceleration and performed system-wide profiling of neuronal cells using Proteome Integral Solubility Alteration (PISA) assay. Dynamic impact leads to both reduction in neuron viability and massive solubility changes in the proteome. The affected proteins map not only to pathways such as cell adhesion, collagen and laminin structures, as well as response to stress, but also to other dense protein networks, such as immune response, complement and coagulation cascades. An energy absorbing material largely rescues the loss of cell viability and dampens proteome solubility changes. The cellular effects are found to be mainly due to the shockwave rather than the g-force acceleration. This study paves the way to introducing a proteome-based shock-meter as well as identifying TBI protein biomarkers and potential drug targets for prevention and intervention.