Carfentanil–xylazine (CX) has been the primary drug combination used for immobilizing free-ranging ungulates in Alaska, US since 1986. We investigated the efficacy of a potential new drug of choice, thiafentanil (Investigational New Animal Drug A-3080). Captive trials indicated that thiafentanil–azaperone–medetomidine could provide good levels of immobilization. However, field trials conducted in October 2013 on free-ranging caribou (Rangifer tarandus granti) calves showed the combination too potent, causing three respiratory arrests and one mortality. The protocol was revised to thiafentanil–azaperone–xylazine (TAX), with good results. The induction time was not significantly different between the two combinations. However, the recovery time was significantly shorter for the TAX group than for the CX group. A physiologic evaluation was performed on 12 animals immobilized on CX and 15 animals on TAX. Arterial blood was collected after induction and again after 10 min of intranasal oxygen supplements (1 L/min). Both groups had significant increases in partial pressure of arterial oxygen after oxygen treatment. There was a concurrent significant increase in partial pressure of arterial carbon dioxide in both groups. Rectal temperature increased significantly in both groups during the downtime, which is consistent with other studies of potent opioids in ungulates. On the basis of our results, we found TAX to be a potential alternative for the current CX protocol for immobilizing free-ranging caribou calves via helicopter darting.