ObjectiveNeurological disorders is an increasing problem in the society. Our study aims to explore the secondary metabolites and evaluate the neuroprotective effect of leave extract of Dodonaea viscosa. MethodsThe ethyl acetate extract was chromatographed and produced one new entity which was characterized by spectroscopy (IR, UV, NMR, MS) studies. This entity was named as (6S, 9R)-vomifoliol-9-β-D-glucopyranosyle (1 -3)- O-α-L-rhamnopyranoside (DVE-8) while the known entities were identified as viscosine (DVE-12), and catechin (DVE-18). The neuroprotective potential of D. viscosa leaves extract was evaluated using the transient middle cerebral artery occlusion (MCAO) method to induce focal cerebral ischemia–reperfusion injury in rats. ResultsThe levels of proinflammatory cytokines such as TNF-α, IL-6, and NF-κB gene expression along with the level of anti-apoptotic Bcl–2, BAX, and caspase–3 gene expression was evaluated. Neurological findings showed a significant reduction in the levels of pro-inflammatory cytokines (TNF-α and, IL-6; both P < 0.05). Also, the NF-κB gene expression was significantly downregulated (P < 0.05). Furthermore, the level of anti-apoptotic Bcl–2 gene expression was significantly upregulated (P < 0.05), whereas the level of BAX and, caspase–3 gene expression was significantly downregulated (P < 0.05). ConclusionThe neuroprotective effect of D. viscosa leaves extract on MCAO-induced ischemic stroke may be due to the anti-inflammation, and anti-apoptosis activities. The findings of the present study may suggest that D. viscosa leaves extract supplementation may serve as valuable adjuvant therapy for neuronal protection.