Detection of cerebral hypoxia-ischemia in infants remains problematic, as current monitors in clinical practice are impractical, insensitive, or nonspecific. Our study develops a multiwavelength spatial domain construct for near-infrared spectroscopy (NIRS) to detect cerebral hypoxia-ischemia and evaluates the construct in several models. The NIRS probe contains photodiode detectors 2, 3, and 4 cm from a three-wavelength, light-emitting diode. A construct determines cerebral O2 saturation based on spatial domain principles. Device performance and construct validity are examined in in-vitro models simulating the brain, and in piglets subjected to hypoxia, hypoxia-ischemia, and hyperoxic conditions using a weighted average of arterial and cerebral venous O2 saturation measured by CO-oximetry. The results in the brain models verify key equations in the construct and demonstrate reliable performance of the device. In piglets, the device measures cerebral O2 saturation with bias ±4% and precision ±8%. In conclusion, this NIRS device accurately detects cerebral hypoxia-ischemia and is of a design that is practical for clinical application.