Two sets of benzenesulfonamide-based effective human carbonic anhydrase (hCA) inhibitors have been developed using the tail approach. The inhibitory action of these novel molecules was examined against four isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules disclosed low to medium nanomolar range inhibition against all tested isoforms. Some of the synthesized derivatives selectively inhibited the epilepsy-involved isoforms hCA II and hCA VII, showing low nanomolar affinity. The anticonvulsant activity of selected sulfonamides was assessed using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) in vivo models of epilepsy. These potent CA inhibitors effectively inhibited seizures in both epilepsy models. The most effective compounds showed long duration of action and abolished MES-induced seizures up to 6 h after drug administration. These sulfonamides were found to be orally active anticonvulsants, being nontoxic in neuronal cell lines and in animal models.