A heritable gain-of-function in BK channel activity has been associated with spontaneous seizures in both rodents and humans. We find that chemoconvulsant-induced seizures induce a gain-of-function in BK channel current that is associated with abnormal, elevated network excitability. Action potential half-width, evoked firing rate, and spontaneous network activity in vitro were all altered 24 h following picrotoxin-induced seizures in layer 2/3 pyramidal cells in the neocortex of young mice (P13-P16). Action potential half-width and firing output could be normalized to control values by application of BK channel antagonists in vitro. Thus, both inherited and acquired BK channel gain-of-functions are linked to abnormal excitability. Because BK channel antagonists can reduce elevated firing activity in neocortical neurons, BK channels might serve as a new target for anticonvulsant therapy.