This retrospective study identified and characterized brain lesions in captive nondomestic felids from a large cat sanctuary. Necropsy reports from January 2002 through December 2018 were examined, and gross images and microscopic slides were reviewed from individual cats, where available. In total, 255 cats met the following inclusion criteria: complete necropsy report available, brain examined grossly or microscopically, and age of >1 mon. Of the 255 cats, 49 cats (19%) were determined to have brain lesions. Eleven different felid species, as well as one captive-bred hybrid (liger), were included in the study, with tigers (Panthera tigris) (55%) and lions (Panthera leo) (18%) being the most common species. Lesions were grouped into six etiologic categories: neoplastic (32%), vascular (26%), inflammatory or infectious (20%), congenital (9%), idiopathic (7%), and metabolic (6%). Not included in these categorized lesions were previously undescribed amphophilic globules in the cerebral cortex of many cats with and without other brain lesions; these were in 95% of lion and 93% of tiger brains where the cerebral cortex was available for histologic examination. These globules were not associated with clinical disease. The histopathologic and gross brain changes documented in this study provide insight into specific diseases and pathologic processes that affect the brains of captive large cat populations.