© 2019 Optical Society of America. Near-infrared spectroscopy (NIRS) is considered ideal for brain monitoring during preterm infancy because it is non-invasive and provides a continuous measure of tissue oxygen saturation (StO2). Hyperspectral NIRS (HS NIRS) is an inexpensive, quantitative modality that can measure tissue optical properties and oxygen saturation (StO2) by differential spectroscopy. In this study, experiments were conducted using newborn piglets to measure StO2 across a range of oxygenation levels from hyperoxia to hypoxia by HS and time-resolved (TR) NIRS for validation. A strong correlation between StO2 measurements from the two techniques was observed (R2 = 0.98, average slope of 1.02 ± 0.28); however, the HS-NIRS estimates were significantly higher than the corresponding TR-NIRS values. These regression results indicate that HS NIRS could become a clinically feasible method for monitoring StO2 in preterm infants.