We chemically restrained fishers (Martes pennanti) as part of a captive-management protocol designed to facilitate veterinary evaluation and treatment, and conditioning on a high-calorie diet before reintroduction in Pennsylvania. We compared the safety and efficacy of ketamine (KET) and medetomidine–ketamine (MED–KET) by monitoring immobilization intervals (induction time, down time, alert time, and recovery time) and physiologic responses (pulse rate, respiration rate, rectal temperature, blood pressure, oxygen saturation, and mean arterial pressure) during restraint. We administered MED–KET at 0.4 mg MED combined with 20.0 mg KET to males and at 0.2 mg MED combined with 10.0 mg KET to females. The x̄ ± SD dosages were MED 0.07 ± 0.008 mg/kg KET 3.7 ± 0.5 mg/kg for males and MED 0.07 ± 0.007 mg/kg KET 3.6 ± 0.3 mg/kg for females. KET alone was administered at 100.0 mg to males and at 50.0 mg to females, resulting in x̄ ± SD dosages of 18.7 ± 1.8 mg/kg for males and 19.2 ± 2.2 mg/kg for females. Mean induction time did not differ between fishers restrained with MED–KET (4.6 min) and KET (4.5 min). However, compared with KET, MED–KET resulted in longer mean down time (36.2 vs. 142.2 min), alert time (40.8 vs. 146.8), and recovery time (81.1 vs. 199.4 min). Fishers that received MED–KET were mildly bradycardic and hypertensive compared with those that received KET. Although KET resulted in increased muscle tension and labored respiration, it would be effective for performing brief, noninvasive procedures for fishers because induction was rapid, recovery was short and calm, anesthesia was not profound, and physiologic response was generally expected on the basis of known drug pharmacology. Medetomidine–ketamine also immobilized fishers effectively, providing rapid induction, physiologic response typical to α₂ agonism, calm recovery, and possibly a plane of anesthesia adequate for invasive procedures such as tooth removal or surgery.