We formulated novel drug combinations of nalbuphine HCl and medetomidine HCl (NalMed), with or without azaperone tartrate, for use in immobilizing Rocky Mountain elk (Cervus elaphus nelsoni) and potentially for other wildlife species. Using the lowest tested nalbuphine dose (0.3 mg/kg) that produced sedation in elk, we initially evaluated a combination of nalbuphine, medetomidine, and azaperone (NalMed-A) for immobilizing adult elk. Based on initial success, we then conducted follow-up trials to assess alternative NalMed formulations successively modified to improve field usability, striving to shorten induction within a dose volume that accommodated practical remote delivery. All NalMed formulations immobilized adult elk; however, combinations with dose volumes that included about 80 mg nalbuphine tended to yield the shortest inductions (mean 6.8 min with, and 7.7 min without, azaperone). Our findings demonstrate that nalbuphine and medetomidine can be combined to yield effective, low-volume (≤2 mL), lightly regulated, reversible drug combinations. Based on results to date, we recommend NalMed-A (40 mg/mL nalbuphine, 10 mg/mL medetomidine, and 10 mg/mL azaperone) dosed at 1.8–2.0 mL for immobilizing adult elk; for recovery we recommend 50 mg naltrexone and 600 mg tolazoline administered intramuscularly (IM) about 5 min in advance of 100 mg atipamezole (divided 25 mg intravenously and 75 mg IM). Further work is under way to explore efficacy in other large mammal species.