Structural segmentation of T1-weighted (T1w) MRI has shown morphometric differences, both compared to controls and longitudinally, following a traumatic brain injury (TBI). While many patients with TBI present with abnormalities on structural MRI images, most neuroimaging software packages have not been systematically evaluated for accuracy in the presence of these pathology-related MRI abnormalities. The current study aimed to assess whether acute MRI lesions (MRI acquired 7–71 days post-injury) cause error in the estimates of brain volume produced by the semi-automated segmentation tool, Freesurfer. More specifically, to investigate whether this error was global, the presence of lesion-induced error in the contralesional hemisphere, where no abnormal signal was present, was measured. A dataset of 176 simulated lesion cases was generated using actual lesions from 16 pediatric TBI (pTBI) cases recruited from the emergency department and 11 typically-developing controls. Simulated lesion cases were compared to the “ground truth” of the non-lesion control-case T1w images. Using linear mixed-effects models, results showed that hemispheric measures of cortex volume were significantly lower in the contralesional-hemisphere compared to the ground truth. Interestingly, however, cortex volume (and cerebral white matter volume) were not significantly different in the lesioned hemisphere. However, percent volume difference (PVD) between the simulated lesion and ground truth showed that the magnitude of difference of cortex volume in the contralesional-hemisphere (mean PVD = 0.37%) was significantly smaller than that in the lesioned hemisphere (mean PVD = 0.47%), suggesting a small, but systematic lesion-induced error. Lesion characteristics that could explain variance in the PVD for each hemisphere were investigated. Taken together, these results suggest that the lesion-induced error caused by simulated lesions was not focal, but globally distributed. Previous post-processing approaches to adjust for lesions in structural analyses address the focal region where the lesion was located however, our results suggest that focal correction approaches are insufficient for the global error in morphometric measures of the injured brain.