The present study aimed to examine the functional and molecular effects of miR‑128 in epilepsy, in order to investigate its potential protective mechanisms. Firstly, miR‑128 expression in rats with lithium chloride‑induced epilepsy was demonstrated to be increased compared with the control rats. Subsequently, results from an in vitro epilepsy model demonstrated that overexpression of miR‑128 promoted nerve cell apoptosis, increased the protein expression of tumor protein p53, BCL2 associated X (Bax) and Cytochrome c, and enhanced caspase‑3/9 activity, whereas it suppressed the protein expression of sirtuin 1 (SIRT1). In addition, these alterations may be reversed by the downregulation of miR‑128. Furthermore, treatment with CAY10602, a SIRT1 agonist, reduced the effects of miR‑128 on nerve cells in vitro. Treatment with pifithrin‑β hydrobromide, a p53 inhibitor, was additionally able to mitigate the effects of miR‑128 in vitro. In conclusion, the present findings indicated that anti‑miR‑128 may exert neuroprotective effects in epilepsy, through the SIRT1/p53/Bax/Cytochrome c/caspase signaling pathway.