Purpose: Pain in the neonate is often challenging to assess but important to control. Physicians often must balance the need for optimal pain control with the need to minimize oversedation and prolonged opioid use. Both inadequate pain control and overuse of opioids can have long-term consequences, including poor developmental outcomes. The aim of this review is to introduce a comprehensive approach to pain management for physicians, nurses, and surgeons caring for critically ill neonates, focusing on nonopioid alternatives to manage procedural pain. Findings: After review, categories of opioid-sparing interventions identified included (1) nonopioid pharmacologic agents, (2) local and regional anesthesia, and (3) nonpharmacologic alternatives. Nonopioid pharmacologic agents identified for neonatal use included acetaminophen, NSAIDs, dexmedetomidine, and gabapentin. Local and regional anesthesia included neuraxial blockade (spinals and epidurals), subcutaneous injections, and topical anesthesia. Nonpharmacologic agents uniquely available in the neonatal setting included skin-to-skin care, facilitated tucking, sucrose, breastfeeding, and nonnutritive sucking. Implications: The use of various pharmacologic and interventional treatments for neonatal pain management allows for the incorporation of opioidsparing techniques in neonates who are already at risk for poor neurodevelopmental outcomes. A multifactorial approach to pain control is paramount to optimize periprocedural comfort and to minimize the negative sequelae of uncontrolled pain in the neonate.