Eleven carbonic anhydrase isoforms are known to be present in different parts of the central nervous system and are involved in signal transduction, cerebral fluid homeostasis, bicarbonate generation, respiratory response to carbon dioxide, seizure activity, and fluid and ion compartmentation. Therefore, carbonic anhydrase inhibitors profoundly influence several neurological therapeutic approaches. Many CAIs, such as acetazolamide, zonisamide, topiramate, lacosamide, and levetiracetam are successfully used in cerebral pathologies. To improve the efficacy, selectivity, and to minimize the side effects, the bespoke medications are engineered using “one-tail approach” and their pharmacological mechanisms of actions are elucidated.