Eugenol (EU), an active principle of cloves, is also widely distributed in various other plants (eg. basil, cinnamon, etc). While its antioxidant and anti-inflammatory properties are well established, biochemical insights related to its neuromodulatory potential in diabetic conditions are not clear. In the present study, initially we investigated its potential to modulate specific biochemical responses in SHSY5Y cells under experimentally -induced hyperglycemic condition. Co-exposure of cells with EU (5–10 μM) not only enhanced the cell viability, but significantly offset glucose -associated oxidative stress (as evidenced by diminished levels of reactive oxygen species and hydroperoxides). Further EU enhanced the reduced glutathione (GSH) levels and also ameliorated the levels of 3 – nitrotyrosine and expression of HSP70. We subsequently examined its efficacy to attenuate biochemical aberrations in brain regions of a streptozotocin (STZ) diabetic rat employing an intervention approach. Brain regions of EU treated (10 mg/kg bw/d, post 6 weeks of STZ) diabetic rats showed diminished levels of oxidative markers and protein carbonyls in both cytosolic and mitochondrial fractions. EU treatment caused enhanced activities of enzymic antioxidants and diminished both GSH and total thiols. Further, activities of complex I – III, succinate dehydrogenase and citrate synthase in brain regions were also significantly restored. Interestingly, EU treatment differentially attenuated the elevated activity of acetylcholinesterase and levels of calcium in brain regions. Collectively, based on the data obtained in in vitro and in vivo models, we hypothesize that EU may be employed as an adjuvant therapeutic molecule to alleviate complications under diabetic conditions.