The immobilization properties and cardiopulmonary effects following intramuscular administration of one of two chemical immobilization agents were compared in the Haitian giant galliwasp (Celestus warreni) in a prospective, blinded, randomized controlled trial. Adult, clinically healthy galliwasps (n = 30) were given a randomly assigned single intramuscular injection of either 15 mg/kg alfaxalone (n = 15) or 40 mg/kg ketamine hydrochloride (n = 15). Heart rate, respiratory rate, and depth classification stage were recorded every 5 min; cloacal temperature was recorded every 15 min to ensure maintenance within this species' preferred optimal temperature range (75–85°F, 24–29°C). Physical examination, radiographs, and phlebotomy were performed in all animals. Alfaxalone given intramuscularly resulted in reliable anesthetic induction, maintenance, and recovery (total duration of anesthesia 57.7 ± 23.6 min, recovery 7.9 ± 7.8 min). Ketamine hydrochloride resulted in variable levels of sedation or anesthesia and a longer recovery (total duration of anesthesia 14 ±17.5 min, recovery 47.9 ± 19.3 min). Heart and respiratory rates remained within clinically acceptable ranges in all lizards using both protocols; however, alfaxalone animals had lower heart rates and respiratory rates associated with increased anesthetic depth as compared to ketamine hydrochloride animals (heart rates: alfaxalone 59.6 ± 13.3 beats/min, ketamine hydrochloride 71.9 ± 7.9 beats/min; respiratory rates: alfaxalone 33.4 ± 16.8 breaths/min, ketamine hydrochloride 50.0 ± 16.2 breaths/min). Duration of anesthesia for alfaxalone-treated galliwasps was longer than previously reported in other studies. This study determined that a single injection of alfaxalone at 15 mg/kg administered intramuscularly can be used for consistent induction and maintenance of anesthesia and prompt recovery in the Haitian giant galliwasp, while ketamine hydrochloride even at 40 mg/kg was unreliable and is not recommended as a sole immobilization agent in the Haitian giant galliwasp.