Sitagliptin (Sita) is a dipeptidyl peptidase-4 inhibitor which has been approved as a curing medicine for Type 2 diabetes (T2D) and has also reported its neuroprotective and antioxidant activity. This article describes the therapeutic effects of Sita on induced rat model of SE by kainic acid (KA) and investigated the antioxidative pathway of sita. Sprague-Dawley male rats were used randomly divided in four groups: vehicle control, KA and Sita + KA in a 5 and 10 mg/kg doses respectively in further groups. SE in rats was induced by the administration of KA in Phosphate buffered saline (PBS) intraperitoneally (IP) in a dose of 15 mg/kg. Seizure intensity, oxidative stress parameters, TUNEL assay, histopathology, and Nrf2/HO-1 expressions were evaluated. Increment in the latency in SE results in delaying the initiation of disease in the pretreated rats by Sita compared to induce group (KA) as well the percentage of occurrence of SE was decreased. The content of MDA elevates whereas the SOD production decreases on administering the KA at various time intervals. Sita shows protective action against the KA-induced SE by reducing the oxidative stress thus inhibiting the change in SOD and MDA was observed after KA administration prior SE onset. Based on the above results, the study explains possible molecular mechanism of Sita. Sita Pretreatment showed significant elevation in expression of Nrf2 and HO-1 proteins in hippocampus region of the brain. Above parameters defines the potential effect of Sita on brain injury occurred due to SE by anti-oxidative pathway.