This systematic review synthesized evidence on sodium thresholds, outcomes, and adverse effects associated with hyperosmolar therapy in adults with moderate-to-severe traumatic brain injury (TBI). Searches across four databases identified 26 studies evaluating mannitol, hypertonic saline (HTS), or both. Hypernatremia definitions varied widely (145–160+ mmol/L), but most cases occurred incidentally rather than through intentional therapeutic elevation. Across cohorts, higher sodium levels—particularly above 155–160 mmol/L—were consistently associated with increased mortality and renal injury. No clear evidence supported intentional therapeutic hypernatremia as beneficial for intracranial pressure control or neurologic outcomes. Findings underscore substantial heterogeneity in practice and the absence of validated upper sodium limits. Future prospective trials are needed to define safe osmotherapy thresholds, differentiate outcomes between HTS and mannitol, and guide individualized treatment strategies.