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Background: Traumatic brain injury (TBI) remains a major clinical challenge in neurosurgery due to its heterogeneous pathophysiology and the limited availability of effective pharmacological interventions. Progesterone and vitamin D have demonstrated neuroprotective and anti-inflammatory properties in preclinical models; however, their translational efficacy in clinical trials remains inconclusive. Clarifying their therapeutic roles may help inform adjunctive strategies in the acute management of neurotrauma. Objectives: To assess the neuroprotective effects of progesterone and vitamin D in enhancing functional recovery following moderate to severe TBI, and to compare the clinical efficacy of these agents based on standardized neurological outcome measures derived from randomized controlled trials (RCTs). Methods: A systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines. Randomized controlled trials (RCTs) were identified through searches of PubMed, EMBASE, Web of Science, and the Cochrane Library, comparing progesterone and/or vitamin D with placebo in patients with traumatic brain injury (TBI). Studies reporting Glasgow Outcome Scale–Extended (GOS-E) outcomes were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using Review Manager version 5.4. Study quality and heterogeneity were assessed. Results: Six RCTs were included: three progesterone trials (n = 1,426) and three vitamin D trials (n = 192). Progesterone showed no significant improvement in functional outcomes compared with placebo (SMD = −0.07; 95% CI: −0.32 to 0.19; p = 0.60; I² = 58%). Vitamin D demonstrated a non-significant trend toward improved outcomes (SMD = 0.37; 95% CI: −0.27 to 1.02; p = 0.26; I² = 78%). Variability in trial design, timing of intervention, and baseline vitamin D deficiency status may have influenced the observed effects. Conclusions: Although neither agent showed standalone efficacy, their safety and complementary mechanisms suggest promise for combinatorial or biomarker-guided approaches. This meta-analysis highlights the need for early, precision-targeted, and stratified neuroprotective trials in TBI care.