Objective: To explore the efficacy and safety of hypertonic saline (HS) resuscitation compared with normal saline (NS) in patients with traumatic brain injury (TBI) complicated by hemorrhagic shock. Methods: A prospective randomized controlled trial was conducted on 296 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] 3–12) and hemorrhagic shock admitted to a Level 1 trauma center from June 2020 to August 2024. Patients were randomly assigned to the HS group (n=148, 7.5% hypertonic saline) and the NS group (n=148, 0.9% normal saline). The primary outcome measures included intracranial pressure (ICP) within 72 hours after resuscitation, cerebral perfusion pressure (CPP), and 28-day mortality. Secondary outcomes covered the incidence of acute lung injury (ALI), length of intensive care unit (ICU) stay, and 6-month Glasgow Outcome Scale (GOS) score. Results: The HS group exhibited significantly lower ICP levels (18.2 ± 3.5 mmHg vs. 23.5 ± 4.1 mmHg, P<0.001) and higher CPP values (72.3 ± 5.8 mmHg vs. 65.7 ± 6.2 mmHg, P<0.001) within 72 hours compared with the NS group. The 28-day mortality rate in the HS group was 16.2% (24/148), which was significantly lower than 27.0% (40/148) in the NS group (P<0.01). The incidence of ALI was comparable between the two groups (10.8% vs. 12.8%, P>0.05). The HS group had a shorter ICU stay (11.5 ± 2.7 days vs. 15.3 ± 3.2 days, P<0.001) and a higher proportion of favorable outcomes (GOS score 4–5) at 6 months (58.1% vs. 45.3%, P<0.05). Conclusion: Hypertonic saline resuscitation can effectively reduce ICP, improve CPP, decrease short-term mortality, and enhance long-term neurological outcomes in patients with TBI combined with hemorrhagic shock, without increasing the risk of ALI.