We evaluated a chamber and nose cone method of isoflurane delivery for anesthetizing eastern gray squirrels (Sciurus carolinensis; summer n = 43, winter n = 48) and Allegheny woodrats (Neotoma magister; summer n = 24, winter n = 13) for use when pain or stress was possible from sampling procedures. Mean induction time for squirrels (from beginning of isoflurane administration to safe removal from trap), was 4.63 ± 0.58 minutes. Squirrels awoke more quickly in summer (1.40 ± 0.15 min) than in winter (3.62 ± 0.24 min) after removal of the nose cone. We manually restrained woodrats and administered the nose cone for 0.5 minutes to each animal. Woodrats awoke after 4.76 ± 0.58 minutes following the final dose of isoflurane for both seasons. These methods are useful for working with small mammals in the field and provide an appropriate anesthetic when there may be more than slight pain or distress.