Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus ( < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi ( < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi ( < 0.01), and 93% and 143% increase in both neocortices ( < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group ( > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi ( < 0.001) and 51% and 92% increase in both cortices ( < 0.001). Kindled + TFS group presented no changes ( > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.