Effective pharmacological methods of pain management are limited for infants who must stay in a hospital’s neonatal intensive care unit (NICU). Preterm infants in particular experience a wide range of stressors in NICUs, such as repeated exposure to painful procedures, and these stressors have in turn been associated with neurodevelopmental impairments. Better pain management strategies could mitigate the stress caused by neonatal procedural pain, but most analgesic treatments currently in use (i.e., fentanyl, morphine) have their own potential for adverse effects in neonates. This chapter will discuss how the endocannabinoid system (ECS) could be a promising target for alleviating pain and distress in preterm infants and review the potential for cannabinoid compounds to mitigate the impact of repeated pain-related stress on neurodevelopment. We place particular focus on the phytocannabinoid cannabidiol, as it is less psychoactive and has minimal adverse effects for adults. Investigating the effects of cannabidiol in comparison to compounds that target some of the same or similar mechanisms of action may produce valuable information about the potential for modulation of the ECS to reduce the effects of neonatal pain-related stress, and by extension improve neurodevelopmental outcomes in preterm infants.