Temporal lobe epilepsy (TLE) with unsatisfactory treatment options requires alternative therapeutic approaches. Stem cells have been recognized as one of the potential curative candidates in various diseases following numerous tests in animals and clinical trials. This study investigated the influence of mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) or adipose tissue (AD-MSCs) on biochemical, molecular and histopathological variations implicated in epileptogenesis of pilocarpine model. Seventy-five adult male Wistar rats were allocated into five groups: (1) placebo group, (2) acute epileptic group, (3) acute epileptic group treated with BM-MSCs, (4) acute epileptic group treated with AD-MSCs and (5) acute epileptic group treated with carbamazepine (CBZ). Brain heat shock protein-70 (HSP-70), S100 calcium binding protein B (S100ß) and caspase-8 levels were assayed by ELISA. Hippocampal toll like receptor-4 (TLR-4) gene expression level was investigated by sqRT-PCR. Histopathological examinations of hippocampal and cortical tissues were carried out. BM-MSCs or AD-MSCs infusion elicated significant decline in HSP-70, S100ß, caspase-8 levels and TLR-4 gene expression level. Micrograph of brain tissue section of acute epileptic rat displayed nucleus pyknosis, while MSCs-treated rats showed almost intact brain histological organization. The outcomes of this research reveal the crucial role of MSCs in seizure control and neural repair via their anti-oxidant, anti-inflammatory and anti-apoptotic properties. Besides, their potentiality in the regulation of blood brain barrier (BBB) integrity. Thus, the present attempt provides critical insights into the mechanism of MSCs therapy in TLE to facilitate the development of cell-based therapy in epileptic patients.