Mutations in methyl CpG binding protein 2 (MeCP2) are linked to Rett syndrome, in which epilepsy is one of the most well-described disorders. However, little is known about the specific role of MeCP2 during epileptogenesis. Our previous study has demonstrated that MeCP2 has a unique control on the development of mossy fiber sprouting (MFS) in the epileptic hippocampus. This study aimed to (1) examine whether MeCP2 affects spontaneous recurrent seizures (SRSs) and cognitive deficits in mice with pilocarpine-induced epilepsy, and (2) profile MeCP2's downstream molecular events. In the dentate gyrus (DG), we found that over-expression or suppression of MeCP2 significantly reduced or increased the frequency, duration, and number of stage 5 seizures of SRSs during the chronic stage after the SE. Over-expression of MeCP2 improved cognitive deficits in TLE mice, while exacerbated cognitive performances were observed following MeCP2 knockdown. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-sequence analyses revealed that MeCP2-targeted genes have far‑reaching impacts on the pathophysiological events during epileptogenesis, including neuron differentiation, neurogenesis, axon guidance, and so on.