Creative music therapy (CMT) has been shown to promote the development of brain function and structure in preterm infants. We aimed to investigate the effect of CMT on cerebral oxygenation and perfusion to examine how the brain reacts to CMT. Absolute levels of cerebrovascular oxygen saturation (StO) were measured in clinically stable preterm-born neonates (n = 20, gestational age: ≥30 weeks and < 37 weeks) using two near-infrared spectroscopy (NIRS)-based tissue oximeters over the right prefrontal cortex and left auditory cortex. We applied the systemic physiology augmented functional NIRS approach. Each CMT session lasted 55 min and involved 9 intervals, including two 10-minute intervals during which the music therapist hummed and held the neonate. We found that CMT-induced changes in cerebrovascular StO, perfusion and systemic physiology (i) could be classified into two groups (group 1: increase in StO during the first singing interval, group 2: decrease in StO), (ii) differed in female neonates compared to male neonates, and (iii) correlated with individual blood haematocrit levels. Our exploratory study (i) demonstrates the impact of CMT on the neonate's physiology and (ii) highlights the need to analyze functional NIRS measurements in neonates separately according to their response pattern to avoid erroneous conclusions, e.g. when only the group average of the signal change is determined.