Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. In addition, there has been a growing appreciation that even repetitive, milder forms of TBI (mTBI) can have long-term deleterious consequences to neural tissues. Hampering our understanding of genetic and environmental factors that influence the cellular and molecular responses to injury has been the limited availability of effective genetic model systems that could be used to identify the key genes and pathways that modulate both the acute and long-term responses to TBI. Using the abundance of genetic tools available in Drosophila, this thesis provides evidence that key molecular pathways that respond to TBI mammalian models, exhibit similar responses and alteration profiles. These identified molecular mechanisms include inflammatory response autophagy alterations, oxidative stress, tau phosphorylation, and changes in neuronal organization and morphology. In addition, using this novel injury paradigm, we demonstrate the powerful utility of Drosophila system to conduct tissue-specific analysis of adult Drosophila head transcriptome following traumatic brain injury. Combined with recent advances in RNA sequencing technologies, our Drosophila model of brain injury can facilitate identification of genes and pathways that are involved in the development and progression of secondary injury mechanisms associated with neurological disorders and development of neurodegeneration following traumatic brain injury.