Abstract Background Dexamethasone-induced neurotoxicity has been previously reported. However, the molecular mechanisms are still not completely understood. Objectives The current work aimed to investigate the modulatory efects of α- and β-adrenergic receptors on dexamethasoneinduced neurotoxicity in rats focused on changes in β-arrestin2 and molecular markers of neural injury in cerebral cortex. Methods Male Wistar rats were subcutaneously injected with dexamethasone (10 mg/kg/day) for 7 days to induce neural injury in the cerebral cortex. The experiment involved 5 groups: control, dexamethasone, carvedilol, propranolol, and doxazosin. In the last 3 groups, drugs were given 2 hours before dexamethasone injection. At the end of experiment, brain samples were collected for measurement of brain derived neurotrophic factor (BDNF), glial fbrillary acidic protein (GFAP), kinase activity of protein kinase B (Akt), diacylglycerol (DAG), α-smooth muscle actin (α-SMA), Smad3, β-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, β-arrestin2 levels in the cerebral cortex were measured using immunohistochemical examination. Results Dexamethasone slightly reduced brain weight and signifcantly decreased BDNF, Akt kinase activity and β-arrestin2 but markedly induced degeneration of cortical neurons and signifcantly increased GFAP, DAG, α-SMA, Smad3, β-amyloid and phospho-tau protein levels compared to controls. Carvedilol, propranolol, and doxazosin reversed all dexamethasoneinduced molecular changes and slightly ameliorated the histopathological changes. Carvedilol signifcantly increased brain weight and β-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups. Conclusion blocking α- and/or β-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct efects on β-arrestin2 levels in the cerebral cortex.