One-third of cancer patients undergoing chemotherapy treatment often display symptoms of depression leading to poor adherence and decreased quality of life. Thus, this study aimed to investigate the possible protective effect of nebivolol against cisplatin-associated depressive symptoms in adult male rats. Nebivolol is a highly cardioselective -adrenergic receptor blocker that possesses endothelium-dependent vasodilator properties and antioxidant capacities. Animals were allocated into four groups. Group one was given aqueous solution of carboxymethyl cellulose and served as control, group two was given nebivolol (10mg/kg p.o., daily), group three was given cisplatin (2mg/kg i.p. once per week) for 10 consecutive weeks and group four was treated with cisplatin concomitantly with nebivolol as per above schedule. Cisplatin-treated rats showed an increase in both depressive-like behaviors in open-field and forced swimming tests. In addition, histopathological examination revealed cortical encephalomalacia along with hippocampal neuronal degeneration and kidney dysfunction. In parallel, cisplatin administration prominently reduced GABA and elevated glutamate levels in the cortical and hippocampal tissues. Furthermore, it resulted in a significant decline in cortical and hippocampal brain-derived neurotrophic factor and nitric oxide contents concomitantly with a marked decrease in endothelial- and an increase in inducible-nitric oxide synthase genes expression. On the other hand, treatment with nebivolol effectively mitigated the aforementioned cisplatin-associated behavioral, biochemical, and histopathological alterations without changing its antitumor activity as evidenced by sulforhodamine B cell survival assay. Taken together, our results suggest that nebivolol may offer a promising approach for alleviating depressive symptoms associated with the use of cisplatin.