Background <p>It has been shown that blood pressure (BP) and peripheral oxygen saturation (SpO₂) influence the outcomes in Traumatic Brain Injury (TBI) patients. This study aims to determine the association between prehospital SpO₂ and in-hospital mortality in hypotensive TBI patients.</p> Methods <p>Prehospital trauma patients who were 18 years old or above with a diagnosis of TBI using ICD 10 codes (S06.0-S06.9) and had prehospital hypotension (systolic blood pressure (SBP) &lt; 100 mmHg for patients aged 50–69 and &lt; 110 mmHg for patients aged 15–49 or over 70 years) recorded from November 2015 to December 2022 in participating PATOS facilities were analyzed. SpO₂ was measured by Emergency Medical Services (EMS) and divided into three levels: normoxia (<i>≥</i> 94%), moderate hypoxia (80–93%), and severe hypoxia (&lt; 80%). The outcomes were survival and disability at hospital discharge. Multivariable logistic regression analysis with interaction analysis was performed to calculate the adjusted odds ratios (AORs) with 95% confidence intervals (CIs).</p> Results <p>Out of 1,210 patients, 777 (64.2%) had normoxia, 319 (26.4%) had moderate hypoxia and 114 (9.4%) had severe hypoxia. Of these, survival to discharge was 92.5%, 74.9%, and 52.6% in the normoxia, moderate hypoxia, and severe hypoxia group, respectively (<i>p</i> &lt; 0.0001). Favorable neurological outcomes in normoxia, moderate hypoxia, and severe hypoxia were 74.1%, 48.9 and 36%, respectively. AORs (95% CI) for survival and favorable neurological outcome compared with severe hypoxia were 3.34 (1.77–6.32)/1.83 (1.04–3.25) in the normoxia group and 2.15 (1.23–3.74)/2.23 (1.31–3.78) in the moderate hypoxia group respectively.</p> Conclusion <p>An initial prehospital saturation of <i>≥</i> 94% was significantly associated with better hospital outcomes in hypotensive TBI patients.</p>