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Brain tissue oxygenation (PbtO₂)-guided therapy can improve the neurological outcome of traumatic brain injury (TBI) patients. With several Phase-III ongoing studies, most of the existing evidence is based on before-after cohort studies and a phase-II randomized trial. The aim of this study was to assess the effectiveness of PbtO₂-guided therapy in a single-center cohort. We performed a retrospective analysis of consecutive severe TBI patients admitted to our center who received either intracranial pressure (ICP) guided therapy (from January 2012 to February 2016) or ICP/PbtO₂-guided therapy (February 2017 to December 2019). A genetic matching was performed based on covariates including demographics, comorbidities, and severity scores on admission. Intracranial hypertension (IH) was defined as ICP > 20 mmHg for at least 5 min. Brain hypoxia (BH) was defined as PbtO₂ < 20 mmHg for at least 10 min. IH and BH were targeted by specific interventions. Mann–Whitney U and Fisher’s exact tests were used to assess differences between groups. A total of 35 patients were matched in both groups: significant differences in the occurrence of IH (ICP 85.7% vs. ICP/PbtO₂ 45.7%, <i>p</i> < 0.01), ICU length of stay [6 (3–13) vs. 16 (9–25) days, <i>p</i> < 0.01] and Glasgow Coma Scale at ICU discharge [10 (5–14) vs. 13 (11–15), <i>p</i> = 0.036] were found. No significant differences in ICU mortality and Glasgow Outcome Scales at 3 months were observed. This study suggests that the role of ICP/PbtO₂-guided therapy should await further confirmation in well-conducted large phase III studies.