Background Hypertonic saline (HTS) and mannitol are frequently utilized in the emergency department (ED) to manage elevations in intracranial pressure (ICP). Objective The objective of this study was to compare the incidence of extravasation injury when HTS or mannitol was administered via peripheral i.v. line (PIV). Methods This retrospective cohort study evaluated adult and pediatric patients given either 3% HTS or mannitol via PIV while in the ED. The primary outcome was extravasation incidence. Results One hundred and ninety-two patients were included, of which 85 (44%) received HTS and 107 (56%) received mannitol. Patients who received HTS were younger (27.5 ± 24.3 years vs. 53.9 ± 22.3 years; p < 0.001); 55.3% of patients given HTS received it for traumatic brain injury (TBI) versus 38.3% of patients given mannitol (p = 0.021); and 44.9% of patients given mannitol received it for intracerebral hemorrhage versus 21.2% of patients given HTS (p = 0.001). There was no incidence of extravasation in either group. Patients who received HTS had lower ICP measurement 24 h post admission (2.107 ± 5.5 mm Hg vs. 4.236 ± 8.1 mm Hg; p = 0.047) and higher Glasgow Coma Scale (GCS) score upon discharge (GCS 14; interquartile range [IQR] 3–15 vs. GCS 3; IQR 3–14.2; p = 0.004). In-hospital mortality was higher in the mannitol group (54.7% vs. 32.9%; p = 0.003). Duration of mechanical ventilation was shorter in those patients who received HTS (1 day; IQR 0–56 days vs. 2 days; IQR 0–56 days; p = 0.023). Conclusions There were no incidences of extravasation among patients given 3% HTS or mannitol. Clinicians should reconsider recommendations to restrict HTS or mannitol to central lines.