Impala (Aepyceros melampus) are a notoriously difficult species to manage in captivity, and anesthesia is associated with a high risk of complications including mortality. The aim of this study was to compare an opioid-based protocol with an α-2 agonist-based protocol. Nine female impala were studied in a random cross-over design. Subjects received either an etorphine–acepromazine (EA) protocol: 15 μg/kg etorphine and 0.15 mg/kg acepromazine, or a medetomidine–ketamine (MK) protocol: 109 μg/kg medetomidine and 4.4 mg/kg ketamine on day 1. Anaesthesia was repeated 3 days later with the alternative protocol. Subjective assessments of the quality of induction, muscle relaxation, and recovery were made by a blinded observer. Objective monitoring included blood pressure, end-tidal CO₂, regional tissue oxygenation, and blood gas analysis. EA provided a significantly quicker (mean EA, 7.17 mins; MK, 17.6 mins) and more-reliable (score range EA, 3–5; MK, 1–5) induction. Respiratory rates were lower for EA with higher end-tidal CO₂, but no apnoea was observed. As expected, blood pressures with EA were lower, with higher heart rates; however, arterial oxygenation and tissue oxygenation were equal or higher than with the MK protocol. In conclusion, at these doses, EA provided superior induction and equivalent muscle relaxation and recovery with apparent improved oxygen tissue delivery when compared to MK.