Crocodilians often require chemical immobilization for safe restraint and veterinary procedures, but there is a paucity of anesthetic studies for these species. The aim of this study was to compare the ability of ketamine (5 mg/kg) versus alfaxalone (5 mg/kg), in combination with dexmedetomidine (50 µg/kg) and midazolam (1 mg/kg) (KDM, ADM), to provide a loss of reflexes and safe orotracheal intubation without producing apnea in American alligators (Alligator mississippiensis). Six 22-month-old captive-hatched American alligators (4.75 ± 0.48 kg and body length of 111.1 ± 9.9 cm) were administered KDM and ADM in the lateral occipital venous sinus in a randomized, crossover design with a 72–80 h washout period between treatments. Physiologic parameters (heart rate, respiratory rate, esophageal and cloacal temperatures, end-tidal CO2) and reflexes (palpebral, cloacal, corneal, righting, withdrawal) were serially assessed throughout the anesthetic episode. Alligators were intubated, and assisted ventilation was provided to apneic animals. Intubation was safely performed within 10 min of administration of ADM and KDM. Respiratory rate was the only physiological parameter to differ between ADM and KDM. The majority (5/6, 83.3%) of alligators administered KDM maintained spontaneous ventilation (P = 0.016) and withdrawal reflexes (P = 0.031), and all alligators (6/6, 100%) given ADM became apneic and lost their withdrawal reflexes in all four limbs. Palpebral, cloacal, and righting reflexes were consistently lost in all animals with both combinations. Recovery time ranged from 5 to 35 min following administration of the reversal agents. Although KDM and ADM both permitted orotracheal intubation, KDM produced less apnea and a lighter plane of anesthesia compared to ADM.