Objective: To explore the efficacy and safety of 20% mannitol versus 3% hypertonic sodium chloride (3% HTS) in patients with cerebral edema secondary to severe traumatic brain injury (sTBI). Methods: A total of 80 sTBI patients complicated with cerebral edema admitted to our hospital between September 2023 and December 2025 were enrolled. Using a random number table, patients were equally allocated into a control group (n=40) and an observation group (n=40). The control group received 20% mannitol at a dose of 0.5 g·kg?¹, rapidly infused intravenously over 15–20 min, once every 8 h. The observation group received 3% HTS at a dose of 4 mL·kg?¹ via peripheral or central venous access by continuous infusion at 20 mL·h?¹, once every 8 h. Both groups were treated for 14 days. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were monitored using an intracranial pressure detector, and cerebral edema volume was measured by computed tomography (CT) before and after treatment. Serum electrolytes and biochemical parameters—including sodium, potassium, chloride, glucose, creatinine, plasma osmolality, and blood urea nitrogen (BUN)—were assayed using an automatic biochemical analyzer before and after treatment. The 3-month prognosis was evaluated using the Glasgow Coma Scale (GCS). Results: After treatment, ICP and cerebral edema volume decreased significantly, while CPP increased in both groups (P<0.05). The observation group exhibited lower ICP and cerebral edema volume, and higher CPP compared with the control group (P<0.05). Compared with baseline, serum sodium and plasma osmolality increased significantly in both groups after treatment (P<0.05), while no marked changes were observed in serum potassium or creatinine levels in either group (P>0.05). Serum chloride remained stable in the observation group (P>0.05) but increased significantly in the control group (P<0.05). Serum glucose decreased and BUN increased in both groups after treatment (P<0.05). Post-treatment comparisons showed that the observation group had higher serum sodium and plasma osmolality, as well as lower serum chloride and BUN than the control group ( P<0.05). No significant intergroup differences were found in serum potassium, glucose, or creatinine levels ( P>0.05). The incidence of complications was significantly lower in the observation group (5.00%, 2/40) than in the control group (20.00%, 8/40; P<0.05). The 3-month favorable prognosis rate was 90.00% (36/40) in the observation group and 80.00% (32/40) in the control group, with no statistically significant difference (P>0.05). Conclusion: Compared with 20% mannitol, 3% hypertonic sodium chloride demonstrates superior efficacy in improving cerebral circulation and reducing cerebral edema in sTBI patients. It induces milder alterations in serum electrolytes and plasma osmolality that better align with clinical requirements, and exhibits a more favorable safety profile.