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Background The efficacy of anterior thalamic nuclei (ANT) deep brain stimulation (DBS) in mitigating epileptic seizures has been established. Though the neuroprotection of ANT-DBS has been illustrated, the seizure mitigating mechanism of ANT-DBS has not been thoroughly elucidated. In particular, the effect of ANT-DBS on neurogenesis has not been reported previously. Method Thirty-two male Sprague Dawley rats were randomly assigned to the following groups: sham-DBS-healthy (HL) (n = 8), DBS-HL (n = 8), sham-DBS-epilepsy (EP) (n = 8) and DBS-EP (n = 8). Normal saline and kainic acid were injected, respectively, into the former and later two groups, and seizures were monitored. One month later, rats received electrode implantation. Stimulation was exerted in the DBS group but not in the sham-DBS group. Next, all rats were sacrificed, and the ipsilateral hippocampus was dissected and prepared for quantitative real time PCR (qPCR) and western blot analysis in order to measure neuronal nuclear (NeuN), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and Ki-67 expressions. Results A 44.4% seizure frequency reduction was obtained after ANT-DBS, and no seizures was observed in healthy rats. NeuN, BDNF, Ki-67 and DCX expression levels were significantly decreased in the epileptic rats compared to healthy rats ( P < 0.01 or P < 0.05). Obvious increases in NeuN, Ki-67 and DCX expressions were observed in epileptic and healthy rats receiving stimulation compared to rats receiving no stimulation (all Ps < 0.01). However, BDNF expression was not affected by ANT-DBS (all Ps > 0.05). Conclusions (1) ANT-DBS reduces neuronal loss during the chronic stage of epilepsy. (2) Neurogenesis is elevated by ANT-DBS in both epileptic and healthy rats, and this elevation may not be regulated via a BDNF pathway. [ABSTRACT FROM AUTHOR]