Background: A significant patent ductus arteriosus (PDA) is a common finding in the first days of life and, if persistent, is associated with an increased morbidity and mortality in the preterm newborn. Objectives: Our aim was to investigate, using near-infrared spectroscopy, the effect of indomethacin on the fractional tissue (cerebral) oxygen extraction (FT_cOE) in a group of preterm newborns undergoing medical treatment for a PDA. Methods: This is a prospective, observational study. A cohort of 18 preterm newborns (<32 weeks) undergoing treatment for a PDA with indomethacin were monitored continuously for mean arterial blood pressure, arterial oxygen saturation (SpO₂) and regional cerebral oxygen saturation (r_cSO₂). Measurements were started 1 h before and continued for 4 h after the first indomethacin dose. A final measurement (1 h) was made within 24 h of completing the full course. FT_cOE = [SpO₂ – r_cSO₂]/SpO₂ was then calculated. To analyze the data, we chose to average the measurements over 1-hour periods. Results: There was a significant increase in the FT_cOE (0.06, 95% CI 0.04–0.09, p < 0.001) noticeable within the 1st hour after the start of indomethacin administration, which peaked in the 2nd hour (FT_cOE increased by 0.08, 95% CI 0.04–0.11, p < 0.001) and lasted for the full 4-hour period measured. Conclusion: Indomethacin, infused over 30 min, significantly increased the FT_cOE in the preterm newborn, the effect lasting at least 4 h. This may represent a protective response to the indomethacin-induced reduction in cerebral blood flow demonstrated by others and warrants further investigation.