Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic-ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous (15)O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq (15)O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and -0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq (15)O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion.