Twelve Australian water dragons (Intellagama lesueurii) presented with acute neurologic dysfunction over a 2-month period. Clinical signs included obtundation, head tilt, loss of proprioceptive and righting reflexes, ataxia, and hyperesthesia. Various treatment protocols had no apparent effect on clinical signs or disease progression, and all 12 animals died or were euthanized. A retrospective review was carried out on tissue sets that were available for nine individuals. Four (44%) of the nine water dragons were classified as cases with long (≥8 days) duration of neurologic signs, and five (56%) of nine were classified as short (≤7 days) duration. On histopathology, all cases with a long duration of neurologic signs had brain lesions characterized by encephalomalacia (i.e., softening of the brain due to necrosis) and gitter cell infiltrates. In the three (33%) water dragons with the longest duration of clinical signs (>13 days), the necrosis was more severe and numerous tortuous vascular formations were present in the brain sections. The five (56%) water dragons with short duration of neurologic signs had similar neurologic symptoms but no histologic brain lesions. The surviving 29 water dragons from the cohort group showed no similar neurologic signs or histopathologic lesions in the 4 yr following this case series. A viral or toxic etiology was suspected.