Background: Opioid abuse is a major health concern in North America. Data have shown an alarming increase in opioid-related deaths and complications, which has shed light on current prescription practices across many specialties, including hand surgery. To that end, we sought to conduct a focused literature review to determine the available modalities to decrease postoperative pain and opioid consumption following upper-extremity nerve decompression procedures, taking advantage of the homogeneity and inherent pain pathways of this specific patient cohort. Methods: A systematic review of the literature was conducted. Primary studies evaluating perioperative and intraoperative modalities for postoperative pain reduction and analgesic consumption following upper-extremity nerve decompression procedures under local anesthesia were included. Studies implementing modalities requiring non–hand surgeon expertise (ie, intravenous sedation), as well as studies that include non–nerve decompression procedures, were excluded. Results: A total of 1478 studies were identified, and 9 studies were included after full-text review. Six studies evaluated intraoperative and 3 studies evaluated preoperative and postoperative modalities. Successful interventions included buffered anesthetic, the use of hyaluronidase, and varying techniques and mixtures for anesthetic administration. No successful preoperative or postoperative modalities were identified. Conclusion: Despite data reporting on the dangers associated with current opioid prescription practices, evidence-based modalities to decrease postoperative pain and opioid consumption are limited in general. Several intraoperative modalities do exist, and nonopioid oral analgesics, standardized opioid protocols, and reduced postoperative prescriptions can be used. Large randomized controlled trials evaluating perioperative modalities for pain reduction are needed to further address this issue.