Introduction: Low brain tissue oxygen tension (PbtO2) has been shown to be an independent factor associated with unfavourable outcomes in traumatic brain injury (TBI). Although PbtO2 provides clinicians with an understanding of ischaemic and non-ischaemic derangements of brain physiology, the value alone can be the result of several factors, including partial arterial oxygenation pressure (PaO2), haemoglobin levels (Hb) and cerebral perfusion pressure (CPP). Methods: This chapter presents a single-centre, retrospective cohort study of 70 adult patients with severe TBI who were admitted to the Neurocritical Care Unit (NCCU) at Addenbrooke’s Hospital (Cambridge, UK) between October 2014 and December 2017. A total of 303 simultaneous measurements of different variables that included (but were not limited to) intracranial pressure (ICP), PaO2, PbtO2, CPP and the fraction of inspired oxygen (FiO2) were considered in this work. We conducted a correlation analysis between all of the variables. We also implemented a longitudinal data analysis of the PbtO2 and PaO2/FiO2 ratio (PF ratio). Results: There were strong and independent correlations between PbtO2 and the PF ratio, and between PbtO2 and PaO2, with adjusted p values of <0.001 for both correlations. After adjustment for ICP, age, sex and the Glasgow Coma Scale (GCS) score, a PF ≤ 330 was shown to be an independent risk factor for a compromised PbtO2 value of <20, with an adjusted odds ratio of 1.94 (95% confidence interval 1.12–3.34) and a p value of 0.02. Conclusion: Brain and lung interactions in patients with TBI patients have complex interrelationships. Our results confirm the importance of employing lung-protective strategies to prevent brain hypoxia in patients with TBI.