Objective: The impact of hypertonic saline (HTS) on the control of increased intracranial pressure (ICP) in head-injured patients undergoing decompressive craniectomy (DC) has yet to be established. The current retrospective study was conducted to compare the effect of HTS and mannitol on lowering the ICP burden of these patients. Methods: We reviewed data on patients who had sustained a traumatic brain injury (TBI) and were admitted to the First People’s Hospital of Kunshan between January 1, 2012, and August 31, 2017. Patients who received only one type of hyperosmotic agent, 3% HTS or 20% mannitol, after DC were included. The daily ICP burden (h/day) and response to the hyperosmolar agent were used as primary outcome measures. The numbers of days in the intensive care unit and in the hospital, and the 2-weeks mortality rates were also compared between the groups. Results: The 30 patients who received 3% HTS only and the 30 who received 20% mannitol only were identified for approximate matching and additional data analyses. The demographic characteristics of the patients in the two groups were comparable, but the daily ICP burden was significantly lower in the HTS group than in the mannitol group (0.89 ± 1.02 h/day vs. 2.11 ± 2.95 h/day, respectively; P = 0.038). The slope of the reduction in ICP in response to a bolus dose at baseline was higher with HTS than with mannitol (P = 0.001). However, the between-group difference in the 2-weeks mortality rates was not statistically significant (2 [HTS] vs. 1 [mannitol]; P = 0.554). Conclusion: When used in equiosmolar doses, the reduction in the ICP of TBI patients achieved with 3% HTS was superior to that achieved with 20% mannitol after DC. However, this advantage did not seem to confer any additional benefit terms of short-term mortality.