Sedation in sea lions exhibiting abnormal neurologic signs may require modification of established sedation protocols because of the likely interaction between effects of the sedative and physiologic changes in diseased animals. The effects of two sedative combinations, 0.07 mg/kg medetomidine and 0.07 mg/kg medetomidine plus 0.2 mg/kg butorphanol, were compared between California sea lions (Zalophus californianus) with signs of neurologic dysfunction (n = 33) and without neurologic signs (n = 8). Sedation depth was scored on a scale of 0 (no effect) to 4 (profound sedation) assessed by response to auditory, tactile, and visual stimuli at the time of perceived maximal sedative effect. In the medetomidine-alone group, sea lions with neurologic signs attained a median sedation score of 4 compared to a median sedation score of 1 in the clinically normal sea lions. Sea lions with and without neurologic signs given medetomidine–butorphanol attained a median sedation score of 4. No statistically significant difference in time to induction and respiratory rate was found between the two sedation protocols in all sea lions. In the sea lions with neurologic signs, the recovery time from medetomidine–butorphanol sedation was prolonged (P < 0.01) and minimum recorded heart rates, although remaining within normal physiologic limits, were lower (P = 0.02) when compared to the sea lions administered medetomidine alone. Muscle jerks were observed in many animals given medetomidine– butorphanol and were detrimental to the diagnostic quality of the electroencephalogram (EEG) recording. Medetomidine alone at a dose rate of 0.07 mg/kg thus provides adequate and safe sedation in sea lions with neurologic signs undergoing EEG evaluation.