Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO₂) are frequently used during vascular and cardiac surgeries as a non-invasive means of assessing brain health; however, signal contamination from extracerebral tissues remains a concern. As an alternative, hyperspectral (hs)NIRS can be used to measure changes in the oxidation state of cytochrome c oxidase (ΔoxCCO), which provides greater sensitivity to the brain given its higher mitochondrial concentration versus the scalp. The purpose of this study was to evaluate the depth sensitivity of the oxCCO signal to changes occurring in the brain and extracerebral tissue components. The oxCCO assessment was conducted using multi-distance hsNIRS (source-detector separations = 1 and 3 cm), and metabolic changes were compared to changes in StO₂. Ten participants were monitored using an in-house system combining hsNIRS and diffuse correlation spectroscopy (DCS). Data were acquired during carotid compression (CC) to reduce blood flow and hypercapnia to increase flow. Reducing blood flow by CC resulted in a significant decrease in oxCCO measured at r_SD = 3 cm but not at 1 cm. In contrast, significant changes in StO₂ were found at both distances. Hypercapnia caused significant increases in StO₂ and oxCCO at r_SD = 3 cm, but not at 1 cm. Extracerebral contamination resulted in elevated StO₂ but not oxCCO after hypercapnia, which was significantly reduced by applying regression analysis. This study demonstrated that oxCCO was less sensitive to extracerebral signals than StO₂