Maternal substance use during pregnancy exposes the fetus to pharmacologic effects and creates the potential for dependence and withdrawal in the neonatal period. Opioids cross the placenta and the fetal blood–brain barrier, resulting in prenatal opioid exposure (POE). The binding of opioids to developing opioid receptors disrupts neurologic, gastrointestinal, and autonomic regulation, leading to the development of neonatal opioid withdrawal syndrome (NOWS), previously referred to as neonatal abstinence syndrome (NAS). The impact of exposure varies by opioid type, dose, duration, and maternal metabolism, resulting in a wide spectrum of neonatal symptoms and severity. In response to the rising incidence of NOWS during the heroin epidemic, scoring systems, including the Finnegan scale, were developed to guide diagnosis and treatment. Infants with POE whose Finnegan scores reached a particular threshold were treated with pharmacologic therapy (typically morphine), which required a prolonged taper. A more recently defined approach, the Eat, Sleep, Console method, focuses on functional well-being rather than a numeric score. Current best practice for management emphasizes non-pharmacologic interventions such as caregiver presence, skin-to-skin care, and a low-stimulation environment, and reserves pharmacologic therapy for severe symptoms. While short-term effects of POE are well documented, including prolonged hospitalization and feeding challenges, long-term neurodevelopmental and behavioral outcomes remain under investigation. Further research is essential to refine screening, optimize management strategies, standardize care, and address social and health disparities affecting families impacted by POE.