AbstractUnderstanding the neurophysiology underlying pain perception in infants is central to improving early life pain management. In this multimodal MRI study, we use resting-state functional and white matter diffusion MRI to investigate individual variability in infants’ noxious-evoked brain activity. In an 18-infant nociception-paradigm dataset, we show it is possible to predict infants’ cerebral haemodynamic responses to experimental noxious stimulation using their resting-state activity across nine networks from a separate stimulus-free scan. In an independent 215-infant Developing Human Connectome Project dataset, we use this resting-state-based prediction model to generate noxious responses. We identify a significant correlation between these predicted noxious responses and infants’ white matter mean diffusivity, and this relationship is subsequently confirmed within our nociception-paradigm dataset. These findings reveal that a newborn infant’s pain-related brain activity is tightly coupled to both their spontaneous resting-state activity and underlying white matter microstructure. This work provides proof-of-concept that knowledge of an infant’s functional and structural brain architecture could be used to predict pain responses, informing infant pain management strategies and facilitating evidence-based personalisation of care.