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Background: We investigated how changes in partial pressure of brain tissue oxygenation (PbtO₂) relate to end-tidal carbon dioxide (EtCO₂) after pediatric traumatic brain injury (TBI). Methods: Dynamic structural equation modeling (DSEM) was used to investigate associations between EtCO₂ and PbtO₂, with positive associations indicating intact CO₂ reactivity of PbtO_2, and negative associations indicating impaired reactivity. Sub-analyses were performed to investigate associations of PbtO₂ to intracranial pressure (ICP), arterial blood pressure (ABP) and cerebral regional oximetry (rSO₂). Results: Among 14 patients, a positive association between PbtO₂ and EtCO₂ was demonstrated (SRC 0.05, 95% CI [0.04, 0.06]), with 9 patients demonstrating intact CO₂ reactivity and 5 patients demonstrating impaired reactivity. Patients demonstrating intact CO₂ reactivity had positive associations between PbtO₂ and ICP (0.22 [0.21, 0.23]), whereas patients with impaired reactivity had negative associations (−0.28 [−0.29, −0.28]). Patients demonstrating intact CO₂ reactivity had negative associations between PbtO₂ and rSO₂ (−0.08 [−0.09, −0.08]), whereas patients with impaired reactivity had positive associations (−0.15 [0.14, 0.16]). Compared to patients with intact CO₂ reactivity_, those with impaired reactivity had increased ICP (<i>p</i> < 0.0000), lower PbtO₂ (<i>p</i> < 0.0000) and higher PRx (<i>p</i> = 0.0134). Conclusion: After TBI, CO₂ reactivity of PbtO₂ can be heterogenous, necessitating further work investigating factors contributing toward impaired reactivity.