In the United States, over 12 months, from June 2019 to May 2020, 81, 230 lives were lost to opioid overdose. As a nation, addressing opioid misuse should take priority (National Safety Council, December 2020). Opioid addiction can occur following routine general surgical admission and as healthcare providers strive to adequately manage perioperative pain, the over-use and over-prescription of opioids have contributed to the opioid epidemic. Utilizing nonopioid analgesics that have a lower addiction potential and fewer side effects can greatly enhance patient recovery and perioperative outcomes (Chia et al., 2020). This systematic review examined the effectiveness of opioid-free anesthesia compared to opioid-inclusive anesthesia in reducing postoperative pain in patients undergoing laparoscopic cholecystectomy. A thorough literature review was performed focusing on cholecystitis and cholelithiasis, pain, postoperative pain, and management following laparoscopic cholecystectomy, multimodal general anesthesia, opioid-free, and opioid-inclusive anesthetic techniques. The framework that guided this systematic review was Good’s middle-range theory of acute pain management. A total of six randomized controlled trials met the inclusion criteria. This systematic review provides promising evidence that opioid-free anesthesia can be an effective and safer alternative to opioid-inclusive anesthesia in reducing side effects, postoperative pain, and opioid consumption in patients undergoing laparoscopic cholecystectomy.