Neonates requiring intensive care and prolonged hospitalizations often undergo procedures and therapies that predispose them to pain, agitation, and delirium. Early recognition and treatment of these symptoms can decrease morbidity and mortality. While nonpharmacologic interventions can be beneficial, they often are insufficient in managing symptoms of pain, agitation, and delirium. Familiarity with the pharmacologic concepts and therapies used to target different pathophysiological mechanisms of pain and agitation will increase the neonatal clinician’s ability to effectively use and tailor these medications to each patient’s needs. In this review, we summarize the pathophysiology, impact, assessment, and management options for each symptom so clinicians can individualize care and use targeted pharmacologic therapies to effectively and safely treat symptoms in various clinical scenarios. We also discuss the importance of protocol use to ensure judicious medication initiation and titration to minimize long-term neurodevelopmental effects of pain, agitation, delirium, and their associated pharmacotherapies.