A major concern with preterm birth is the risk of neurodevelopmental disability. Poor cerebral circulation leading to periods of hypoxia is believed to play a significant role in the etiology of preterm brain injury, with the first three days of life considered the period when the brain is most vulnerable. This study focused on monitoring cerebral perfusion and metabolism during the first 72 h after birth in preterm infants weighing less than 1500 g. Brain monitoring was performed by combining hyperspectral near-infrared spectroscopy to assess oxygen saturation and the oxidation state of cytochrome c oxidase (oxCCO), with diffuse correlation spectroscopy to monitor cerebral blood flow (CBF). In seven of eight patients, oxCCO remained independent of CBF, indicating adequate oxygen delivery despite any fluctuations in cerebral hemodynamics. In the remaining infant, a significant correlation between CBF and oxCCO was found during the monitoring periods on days 1 and 3. This infant also had the lowest baseline CBF, suggesting the impact of CBF instabilities on metabolism depends on the level of blood supply to the brain. In summary, this study demonstrated for the first time how continuous perfusion and metabolic monitoring can be achieved, opening the possibility to investigate if CBF/oxCCO monitoring could help identify preterm infants at risk of brain injury.