Abstract Background Acute blood loss linked to severe hypovolemia and hemorrhagic shock is a critical condition in pediatric intensive care. This study was to investigate the role of various fluid resuscitation approaches to cerebral tissue oxygenation using a piglet model of hemorrhagic shock. Methods Thirty piglets received blood removal to induce hemorrhagic shock, and then were randomly assigned to a control group (no treatment), a control-normal saline (NS) group (treated with bolus normal saline 10 mL/kg only), or one of three treatment groups treated with 15 mL/kg/dose fluid every 30 min with either whole blood (WB), lactated Ringer’s solution (LR), or NS in addition to an initial bolus of saline. The piglets’ physiological profiles, arterial blood gases, and regional cerebral oxygen saturation (rScO 2) levels were recorded, fractional tissue oxygen extraction was calculated, and blood hemoglobin levels were measured. Results The results showed that no matter whether treated with only one dose of bolus NS (control-NS group) or with extra WB, LR, or NS, all the treated animals had a significantly higher survival rate, mean arterial blood pressure (MAP), arterial oxygen tension, arterial oxygen saturation, and rScO 2 than the control group ( p < 0.05). Animals treated with WB all survived the full experimental period, and their hemoglobin levels, MAP, and rScO 2 were the highest comparing to all other groups ( p < 0.05). Conclusion Effective resuscitation using a high concentration of inspired oxygen and adequate fluid infusion, either as a single-dose bolus of NS or combining this with a subsequent transfusion of WB, LR, or NS, helped to stabilize the cardiovascular condition of the tested young subjects and improved cerebral tissue oxygenation over the emergent first four hours. Furthermore, WB was the best fluid choice when used in addition to the bolus NS challenge for maintaining better brain tissue oxygenation when treating hemorrhagic shock.