Background: Traumatic brain injury has a crippling impact on sufferers’ quality of life, and numerous therapy techniques are being researched to address this problem. In this study, we compared the superiority of HS against mannitol as one such element of treating TBI patients. Objective: To compare the efficacy of hypertonic saline and mannitol and demonstrate superiority of one group over the other. Method: Our meta-analysis included only randomized controlled trials that compared the efficacy of mannitol and hypertonic saline in the treatment of traumatic brain injury. The literature search was done using a variety of databases, like Google Scholar, PubMed, and the Cochrane Library. From each of the included RCTs, accurate data extraction, bias risk assessment, and statistical analysis were carried out. Result: There are 748 patients among the 15 RCTs. Our primary outcomes are mortality and functional outcomes, and our secondary outcomes include treatment failure, osmolality, intracerebral pressure (ICP), cerebral perfusion pressure (CPP), serum sodium (Na), partial pressure of oxygen in brain tissue (PBTO2), duration of elevated ICP, mean arterial pressure, hematocrit level, and central venous pressure. The comparison showed non-significant results for mortality (RR = 0.73, 95% CI 0.49–1.08; p = 0.12) and functional outcome (RR = 1.15, 95% CI = 0.74–1.80; p = 0.53). HS is linked to higher Na levels (RR = 4.55, 95% CI 1.34–7.76, P = 0.005, I2 = 96%). Despite performing a sensitivity analysis due to the heterogeneities in our various outcomes, the findings were still unreliable. Conclusion: Our study revealed inconsequential trends for HS and mannitol, and no conclusion was made. We believe the two medications to be equally effective, but there is still opportunity for improvement as more studies are carried out. Eventually, a conclusive decision can be reached in the future.