Perioperative cerebral hypoperfusion/ischemia is considered to play a pivotal role in the development of secondary traumatic brain injury (TBI). This prospective randomized, double-blind, controlled study investigated whether magnesium sulfate (MgSO4) infusion was associated with neuroprotection in maintaining regional cerebral oxygen saturation (rSO2) values in patients with mild TBI undergoing general anesthesia. Immediately after intubation, we randomly assigned patients with TBI to receive either intravenous MgSO4 (30 mg/kg for 10 min, followed by a continuous infusion of 15 mg/kg/h) or a placebo (saline) during surgery. We also implemented an intervention protocol for a sudden desaturation exceeding 20% of the initial baseline rSO2. The intraoperative rSO2 values were similar with respect to the median (left. 67% vs. 66%, respectively; p = 0.654), lowest, and highest rSO2 in both groups. The incidence (left 31.2% vs. 24.3%; p = 0.521) and duration (left 2.6% vs. 3.5%; p = 0.638) of cerebral desaturations (the relative decline in rSO2 < 80% of the baseline value) were also similar for both groups. Although the patients suffered serious traumatic injuries, all critical desaturation events were restored (100%) following stringent adherence to the intervention protocol. Intraoperative remifentanil consumption, postoperative pain intensity, and fentanyl consumption at 6 h were lower in the MgSO4 group (p = 0.024, 0.017, and 0.041, respectively) compared to the control group, whereas the satisfaction score was higher in the MgSO4 group (p = 0.007). The rSO2 did not respond to intraoperative MgSO4 in mild TBI. Nevertheless, MgSO4 helped the postoperative pain intensity, reduce the amount of intraoperative and postoperative analgesics administered, and heighten the satisfaction score.