Background: Neonates, particularly those born preterm, undergo multiple painful procedures in neonatal intensive care units (NICUs). Evidence shows that such exposures are not transient but induce long-lasting neuroimmune and epigenetic changes, creating a phenomenon termed “pain memory,” with effects on brain development and behavior. Methods: This scoping review was conducted using a PICOT framework. Population: neonates (preterm and term); Intervention: procedural or surgical pain and its management (pharmacological and non-pharmacological); Comparator: infants with lower/no pain exposure or alternative management; Outcomes: (a) biological mechanisms, (b) neurodevelopmental and behavioral sequelae such as anxiety and dysregulation, (c) demographic/sex-specific differences, (d) clinical management strategies; Timeframe: immediate to long-term follow-up. Searches of PubMed, Embase, Web of Science, Scopus, and Cochrane (1990-May 2025) identified 342 records. Following duplicate removal, 270 abstracts were screened, 90 full texts were reviewed, and 30 studies were included. Screening was performed independently by two reviewers, with conflicts resolved by a third adjudicator. Data were charted for design, demographics, interventions, outcomes, and limitations. Results: Studies have revealed that early nociceptive injury primes microglia and reprograms macrophages through epigenetic pathways. Clinical cohorts showed cumulative pain exposure associated with altered thalamic/cortical development, reduced white-matter integrity, lower cognitive scores, and higher risks of anxiety and behavioral dysregulation. Females exhibited stronger immune-mediated programming, while extremely preterm infants were most vulnerable. Non-pharmacological strategies (skin-to-skin, breastfeeding, sucrose), alongside judicious pharmacological use, reduced acute pain and may influence long-term outcomes. Conclusions: Neonatal pain memory represents durable biological and behavioral alterations. Multimodal, family-centered approaches should be standard, while future trials must clarify whether early interventions reduce later neurodevelopmental risks and how sex-specific mechanisms can inform personalized care.

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