Traumatic brain injury (TBI) is a common source of neurological injury in civilian and military populations. In addition to neurological damage associated with the primary impact, brain regions neuroanatomically connected to the site of impact can undergo anterograde, retrograde and trans-synaptic degeneration, termed diaschisis. We used controlled cortical impact in mice to model human TBI. Local injury was associated with distal diaschisis lesions that developed in brain regions anatomically connected to the injured cortex. 7 days after injury, histochemistry documented broadly distributed lesions particularly in the contralateral cortex and ipsilateral thalamus and striatum. Astrocytosis and microgliosis were noted in several neural pathways that also showed silver-stained cell processes and bodies. Contralateral cortical silver positive diaschisis lesions exhibited loss of both phosphorylated and non-phosphorylated neurofilament staining but overall preservation of MAP-2 staining. Thalamic lesions showed loss of MAP-2 and non-phosphorylated neurofilament along with moderate loss of phosphorylated neurofilament. One animal demonstrated contralateral cerebellar degeneration at 7 days post injury. 21 days after injury, gliosis had quelled, however persistent silver staining was observed. Using a serial section technique, we were able to perform electron microscopy on regions characterized at the light microscopy level. Cell bodies and processes silver positive at the light microscopy level showed hydropic disintegration consisting of: loss of nuclear heterochromatin; dilated somal and neuritic processes with a paucity of subcellular organelles and increased numbers of electron dense membranous structures. The cell membrane itself was still intact 21 days after injury. The full biochemical nature of diaschisis lesions may help decipher the etiology of other neurodegenerative disorders.