Fentanyl is commonly used in critically ill patients receiving extracorporeal membrane oxygenation (ECMO). Fentanyl’s lipophilicity and protein binding may contribute to a sequestration of the drug in the ECMO circuit. Hydromorphone lacks these characteristics potentially leading to a more predictable drug delivery and improved pain and sedation management among ECMO patients. This study compared hydromorphone to fentanyl in patients receiving ECMO. This retrospective study included adult patients receiving ECMO for ≥48 hours. Patients were excluded if they required neuromuscular blockade, received both fentanyl and hydromorphone during therapy, or had opioid use before hospitalization. Baseline characteristics included patient demographics, ECMO indication and settings, and details regarding mechanical ventilation. The primary outcome was opioid requirements at 48 hours post cannulation described in morphine milligram equivalent (MME). Secondary endpoints included 24-hour opioid requirements, concurrent sedative use, and differences in pain and sedation scores. No differences were noted between the patients receiving fentanyl (n = 32) or hydromorphone (n = 20). Patients receiving hydromorphone required lower MME compared to fentanyl at 24 hours (88 [37–121] vs. 131 [137–227], p < 0.01) and 48 hours (168 [80–281] vs. 325 [270–449], p < 0.01). The proportion of within-goal pain and sedation scores between groups was similar at 24 and 48 hours. Sedative requirements did not differ between the groups. Patients receiving hydromorphone required less MME compared to fentanyl without any differences in sedative requirements, or agitation-sedation scores at 48 hours. Prospective studies should be completed to validate these findings.