Different paradigms for neurocritical care of traumatic brain injury (TBI) have emerged in conjunction with advanced neuromonitoring technologies and derived metrics. The priority for optimizing these metrics is not currently clear. The goal of this study was to determine whether achieving cerebral perfusion pressure (CPPopt) also improves other metrics like brain oxygenation and brain blood flow. The authors performed a retrospective analysis of high-frequency data from patients with TBI who were treated at a single center and who had partial pressure of brain oxygen (PbtO2) measurements and/or brain blood flow measurements, while also undergoing intracranial pressure (ICP) monitoring. CPPopt was not calculated or targeted during patient care, but was retrospectively computed, as was the difference between the observed CPP and CPPopt. A total of 22 patients with ICP, PbtO2, and/or brain blood flow monitoring were included in the analysis, and 245.7 days of measurements obtained every second were analyzed including 6,748,866 PbtO2 measurements, 3,296,405 blood flow measurements, and 10,264,770 ICP measurements. The data obtained every second were averaged by minute for analysis. In summative data, PbtO2 measurements peaked near CPPopt and were not improved above CPPopt. Blood flow measurements remained stable near CPPopt, decreased below it, and increased when CPP exceeded CPPopt. ICP decreased linearly with CPP without a specific relationship with CPPopt. In an inverse analysis, the percentage of CPP values at CPPopt, although significantly higher on the favorable side of contemporary treatment thresholds of PbtO2, ICP, and blood flow, was not found to be strongly correlated with the mean values of the physiological measurements obtained every minute (r = 0.27, r = 0.11, and r = 0.47 for ICP, PbtO2, and blood flow, respectively; p < 0.0001). Although CPPopt was not targeted in the patients in this study, CPPopt was a physiologically significant value based on concurrent measurements of PbtO2 and blood flow. In summative data, achievement of CPPopt was associated with optimized PbtO2 and blood flow. Conversely, the correlation between achievement of CPPopt and the mean measurement value was not strong, strengthening the significance of CPPopt. In individual patients, achieving CPPopt is not always associated with optimal PbtO2 or blood flow. Further research should explore these relationships in treatment paradigms that specifically target CPPopt. These data do not support the premise that targeting and achieving CPPopt obviates the need for concurrent PbtO2 and blood flow monitoring. Although these data suggest that targeting CPPopt may be an appropriate initial treatment strategy, they do not provide evidence that CPPopt should be targeted with highest priority.