This case-control study examines the association between multimodal analgesia administration and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction and investigates whether multimodal analgesia alters the duration of stay in the postanesthesia care unit. Question Is there an association between the administration of oral celecoxib, gabapentin, and/or tramadol hydrochloride before surgery and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction? Findings In this case-control study of 149 patients who received oral celecoxib, gabapentin, and/or tramadol medications before surgery and 208 patients who did not, opioid use and the duration of stay in the postanesthesia care unit were reduced in patients who received the medications. Meaning The findings of this case-control study suggest that the use of a multimodal analgesia regimen, such as celecoxib, gabapentin, and/or tramadol, may decrease opioid use during the perioperative period and shorten the duration of stay in the postanesthesia care unit. Importance The opioid epidemic has reignited interest in opioid-sparing strategies in managing pain. However, few studies have focused on opioid use during perioperative care in patients undergoing head and neck surgery with free flap reconstruction. Objectives To examine the association between multimodal analgesia (MMA) administration and perioperative opioid requirements in patients undergoing head and neck surgery with free flap reconstruction and to investigate whether MMA alters the duration of stay in the postanesthesia care unit (PACU). Design, Setting, and Participants In this retrospective case-control study, data were collected between April 1, 2016, and December 31, 2017. The study was conducted at a single cancer center in the United States. Participants were 357 patients 18 years or older scheduled for head and neck surgery with free flap reconstruction. Exposures Patients in the treatment group received oral celecoxib, gabapentin, and/or tramadol hydrochloride before surgery. Control group patients did not receive any of these medications. Main Outcomes and Measures The amount of opioid administered in the operating room and in the PACU was converted to morphine equivalent daily dose (MEDD) for comparison between the 2 groups. The duration of stay in the PACU was based on the start time and end time of PACU care recorded by nurses in the PACU. Results In total, 149 patients (mean [SD] age, 60.3 [13.7] years; 104 [69.8%] men) were included in the treatment group, and 208 patients (mean [SD] age, 64.2 [13.6] years; 146 [70.2%] men) were included in the control group. The mean (SD) MEDD of opioid given during surgery was 51.7 (19.8) in the treatment group and 67.9 (24.7) in the control group, for a difference in the means (treatment vs control) of -16.17 (95% CI, -20.81 to -11.52). In the PACU, the mean (SD) MEDD of opioid given was 11.7 (13.3) in the treatment group and 14.9 (15.7) in the control group, for a difference in the means (treatment vs control) of -3.22 (95% CI, -6.40 to -0.03). The MMA treatment remained largely associated with reduced amount of opioid given during surgery, in the PACU, and both combined after controlling for other important factors. Conclusions and Relevance This case-control study found that the patients who received MMA before head and neck surgery with free flap reconstruction required less opioid medication. The treatment group also had shorter duration of stay in the PACU compared with the control group.