The objectives of this clinical study were to compare the effectiveness and safety of medetomidine-ketamine-midazolam (MKM) versus medetomidine-ketamine-butorphanol (MKB) for immobilization of captive red kangaroos (Osphranter rufus). Twenty red kangaroos were randomly immobilized for routine treatments using intramuscular injection of MKM (0.065 ± 0.004, 2.2 ± 0.3, and 0.12 ± 0.04 mg/kg, respectively) or MKB (0.070 ± 0.015, 2.3 ± 0.5, and 0.23 ± 0.05 mg/kg, respectively) (n = 10/group). Induction, immobilization, and recovery times were recorded; vital signs monitored; and quality of induction, immobilization, and recovery scored using a single-blinded design. Oxygen was not supplemented. For reversal, atipamezole at five times the medetomidine dosage was administered intramuscularly (both groups), and flumazenil (0.020 ± 0.003 mg/kg; MKM) or naltrexone (0.23 ± 0.05 mg/kg; MKB) were administered intravenously. Induction time was significantly shorter in the MKB group versus the MKM group (7:26 ± 04:22 and 11:54 ± 04:50 minutes, respectively). Induction quality in both groups was rated “excellent” and immobilization quality was “excellent” in MKM and “very good” in MKB. Heart rate was significantly lower and hemoglobin oxygen saturation (SpO2) was significantly higher in the MKM versus the MKB group. However, SpO2 < 90% occurred with both protocols. Following antagonists administration, recovery time and quality were 17:40 ± 08:33 minutes and “very good” in the MKM group, and 14:28 ± 05:27 minutes and “excellent” in the MKB group, respectively. Both protocols provided smooth induction, good immobilization, and generally quick recovery. MKB is recommended for shorter induction time. Oxygen supplementation should be available with both protocols.