Decompressive craniectomy (DC) is a vital intervention for severe traumatic brain injury (TBI), especially in refractory intracranial hypertension. While effective in lowering intracranial pressure (ICP), its impact on long-term functional outcomes and survival with disability remains debated. This study aimed to analyze clinical outcomes for TBI patients who underwent DC at a Greek tertiary hospital and identify prognostic factors. This retrospective study included 144 patients who underwent DC from 2014 to 2024. Univariate analyses evaluated associations with early and late outcomes and in-hospital mortality. Exploratory multivariable logistic regression models were also constructed. The mortality rate was 41%, with 32.4% of patients achieving a favorable early outcome and 31.4% achieving a favorable late outcome. Both age and initial neurological status were significantly associated with early and late outcomes (p ≤ 0.01). Abnormal pupillary response was significantly associated with unfavorable outcome and in-hospital mortality in a univariate analysis. In exploratory multivariable models, older age and lower Glasgow Coma Scale–Pupils (GCS-P) scores were independently associated with unfavorable early and 12-month outcomes and in-hospital mortality. Treatment during the coronavirus disease 2019 (COVID-19) pandemic period was associated with higher in-hospital mortality, an association that may reflect pandemic-related healthcare system pressures rather than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Larger multicenter studies are needed to develop and validate reliable prognostic models.