Emerging evidence suggests that hypertonic saline (HTS) is efficient in decreasing intracranial pressure (ICP). However there is no consensus about its interaction with brain hemodynamics and oxygenation. In this study, we investigated brain response to HTS bolus with multimodal monitoring after severe traumatic brain injury (TBI). We included 18 consecutive TBI patients during 10 days after neurocritical care unit admission. Continuous brain monitoring applied included ICP, tissue oxygenation (PtO2) and cerebral blood flow (CBF). Cerebral perfusion pressure (CPP), cerebrovascular resistance (CVR), and reactivity indices related to pressure (PRx) and flow (CBFx) were calculated. ICM + software was used to collect and analyze monitoring data. Eleven of 18 (61%) patients developed 99 episodes of intracranial hypertension (IHT) greater than 20 mm Hg that were managed with 20% HTS bolus. Analysis over time was performed with linear mixed-effects regression modelling. After HTS bolus, ICP and CPP improved over time (p < 0.001) following a quadratic model. From baseline to 120 min, ICP had a mean decrease of 6.2 mm Hg and CPP a mean increase of 3.1 mmHg. Mean increase in CBF was 7.8 mL/min/100 g (p < 0.001) and mean decrease in CVR reached 0.4 mm Hg*min*100 g/mL (p = 0.01). Both changes preceded pressures improvement. PtO2 exhibited a marginal increase and no significant models for time behaviour could be fitted. PRx and CBFx were best described by a linear decreasing model showing autoregulation recover after HTS (p = 0.01 and p = 0.04 respectively). During evaluation, CO2 remained constant and sodium level did not exhibit significant variation. In conclusion, management of IHT with 20% HTS significantly improves cerebral hemodynamics and cerebrovascular reactivity with recovery of CBF appearing before rise in CPP and decrease in ICP. In spite of cerebral hemodynamic improvement, no significant changes in brain oxygenation were identified.