Chemical immobilization is a key aspect of wildlife management. To minimize dose-dependent adverse effects, immobilization protocols often include two or more synergistic agents, which allows for reductions in individual drug dosages. Free-ranging bighorn sheep (Ovis canadensis) in Canada (n = 74) were remotely injected with a combination of medetomidine (0.16 ± 0.04 mg/kg) and ketamine (4.0 ± 1.4 mg/kg) (MK), or combination of medetomidine (0.14 ± 0.06 mg/kg), azaperone (0.21 ± 0.11 mg/kg), and alfaxalone (0.45 ± 0.21 mg/kg) (MAA). Once recumbency was achieved, arterial blood samples were collected and immediately analyzed for blood gas and acid-base status. Rectal temperature, heart rate, and respiratory rate were recorded upon recumbency and throughout anesthesia at 5–15 min intervals. At conclusion of the procedures, medetomidine was reversed by intramuscular atipamezole at five times the medetomidine dose. Induction times (mean ± standard deviation) of animals that became immobilized with one dart (8.7 ± 3.2 min, 7.3 ± 3.9 min) and recovery times of all animals (3.4 ± 1.5 min, 3.9 ± 1.6 min) were not significantly different between MK and MAA groups, respectively. Both MK and MAA groups experienced severe hypoxemia (PaO₂ 42 ± 9 mmHg, 40 ± 10 mmHg, respectively). PaCO₂ was significantly higher (P = 0.0248) in the MK group (median 54 mmHg) than the MAA group (median 48 mmHg) with a trend towards lower pH (7.40 vs 7.42, respectively, P = 0.07). Initially, MK animals had higher heart rates than MAA animals (median 49 vs 40 beats/min), which decreased over time. In bighorn sheep, both MK and MAA produced reliable, reversible immobilization with smooth inductions and recoveries. However, less respiratory depression was seen with MAA than MK.