Heterogeneity associated with traumatic brain injury (TBI) outcomes necessitates validated controls to differentiate pathophysiological events from experimental methodology. While craniectomies are commonly used in TBI research, inadvertent dura disruption can result in structural deficits, impacting cellular function and neurobehavioral outcomes. Thus, there is a critical need to evaluate the effect of craniectomy on neurological outcomes to develop robust experimental controls and improve pre-clinical TBI research. In this study, craniectomy mice undergoing surgical and anesthetic intervention were assessed against naïve mice for neurological deficits and pathophysiological dysfunction. T2-weighted magnetic resonance imaging confirmed that no lesions or cavities were observed postcraniectomy. However, the cranial defect induced midline shifting over time, which might contribute to poorer behavioral outcomes in the novel object recognition assessment. Immunohistochemical analysis demonstrated an increase in GFAP and Iba1, indicating craniectomy elicited an inflammatory response. Indeed, neuroinflammation led to an increase in neuronal cell death, as measured by increases in α-II-spectrin breakdown products. However, craniectomy mice also presented with decreases in LC3BII and SQSTM1 expression, indicating an inhibition of autophagy. Last, craniectomy contributed to the altered expression of several tight junction proteins, including occludin and claudin-1/5, suggesting the blood-brain barrier was perturbed. Overall, the deficits associated with craniectomy preclude its use as an adequate sole control for TBI research, as craniectomy limits translational insights into the neurological changes observed in TBI. Additionally, these results support the need for the use of closed-head injury models where uninjured control mice do not show significant confounding minor injury patterns.