Temporal lobe epilepsy (TLE) is a neurological disorder associated with spontaneously recurrent seizures with about 30% of the patients exhibiting pharmacoresistant. Thus, it is imperative to understand the molecular mechanisms underlying the pathogenesis of TLE to develop an effective treatment strategy. Several neurological disorders are associated with Histone deacetylase 4 (HDAC4) dysregulation, but its specific molecular substrates and the precise mechanism by which it contributes to TLE are unknown. Thus, in our study, we used the lithium-pilocarpine model of TLE and samples resected from epileptic patients to examine region-specific differences in HDAC4 expression and its interaction with a non-histone substrate --serum response factor (SRF). The mRNA and protein levels of HDAC4 and SRF along with their interaction in the hippocampus, anterior temporal lobe, and cortex were determined using qRT-PCR, western blotting, and co-immunoprecipitation respectively. An immunofluorescence assay was used to determine the cell-specific expression. Our results for the first time revealed a region-specific alteration in the levels of HDAC4 in both the animal model and patient samples with a significant increase in HDAC4 expression and cytoplasmic accumulation in the epileptic hippocampus suggesting that HDAC4 might be playing a crucial role in the establishment of distinct epileptogenic networks in the brain and its potential as a therapeutic target. Moreover, SRF was identified as a functional interacting partner of HDAC4 and their interaction was found to be decreased in the epileptic hippocampus suggesting a dysregulation of the HDAC4-SRF axis in TLE which could be a possible contributing factor in its pathogenesis.