A transcranial photoacoustic (PA) imaging can non-invasively quantify graded oxyhemoglobin (HbO 2 ) saturation changes at the superior sagittal sinus (SSS) and brain tissue through intact skull and scalp of large animal models and humans, which strongly implies its potential to address urgent clinical problems to identify brain distress in patients. However, effective signal processing to compensate for substantial transcranial signal attenuation is still desired to secure high imaging contrast. In this study, we present a spectral system denoising scheme for the spectroscopic PA neuroimaging using in vivo neonatal piglets, which well resembles the skull thickness and neurophysiology of term human neonates.