Neonatal abstinence syndrome (NAS) highlights the intricate interplay between maternal substance use during pregnancy and the challenges neonates face from the distressing global opioid crisis. This comprehensive review captures the multilayered landscape of NAS, encircling its underlying mechanisms, epidemiology, diagnostic intricacies, clinical manifestations, continuing developmental impacts, treatment paradigms, and the crucial role of multidisciplinary care. The core pathophysiology of NAS involves the transplacental passage of addictive substances, activating chemical dependence in the maturing fetus, which is characterized by neurotransmitter dysregulation, neuroadaptations, and receptor sensitization. A diverse clinical presentation ranges from central nervous system hyperactivity and autonomic dysregulation to gastrointestinal manifestations, necessitating homogenous assessment tools such as the Finnegan Neonatal Abstinence Scoring System. The demand for a multilayered approach is essential for comprehensive management, involving pharmacological interventions like morphine or methadone and non-pharmacological strategies such as swaddling. The complications of NAS are not only limited to but are also well beyond infancy, leading to behavioral, longstanding cognitive, and socioemotional consequences. Addressing these developmental arcs demands decisive longitudinal monitoring and early interventions. NAS management is fundamentally multidisciplinary, requiring the teamwork of nurses, social workers, psychologists, pediatricians, and neonatologists. Apart from the clinical realm, managing the psychosocial needs of families traversing NAS requires resources and empathy. A crucial comprehensive approach is essential to confront the challenges and limitations of NAS. From early identification and prevention to longstanding support through pharmacological, non-pharmacological, and psychological channels, it creates a holistic structure that emerges as the basis for understanding the complicated relationship between maternal substance use and its impact on neonates. An amalgamation of community engagement, society, policy initiatives, and medical expertise is essential to mitigate the repercussions of NAS and adopt healthier outcomes for affected infants.