Cisplatin ototoxicity is a major dose-limiting factor in the treatment of several neoplastic diseases. Oxidative stress might play an important role of pathogenesis of cisplatin ototoxicity. The aim of this study was to examine protective effect of mirtazapine against cisplatin-induced ototoxicity and DNA damage. A total of 16 albino male guinea pigs were assigned into 3 groups: control, cisplatin (10 mg/kg, i.p.), cisplatin (10 mg/kg, i.p.) plus mirtazapine (10-15 mg/kg, p.o.) for 7 days. After sacrification of all animals by high-dose anesthesia, the cochleae were removed and subjected to histological (the left ear) and biochemical (the right ear) analyses. Cisplatin administration increased malondialdehyde content by 3.01-fold, depressed glutathione level by 64% and elevated 8-hydroxy-2-guanine level by 140% in the cochlear tissue as compared to the control group (p<0.05 for all). Mirtazapine administration reversed the effect of cisplatin administration on the cochlear measurements. Mirtazapine administration alleviated damages caused by cisplatin on the outer hair cells, spiral ganglion cells and Reissner membrane. In conclusion, mirtazapine alleviated cisplatin-induced oxidative stress and DNA damage through exerting antioxidant effect in guinea pigs cochleae. Antioxidant property of mirtazapine may increase effective usage of cisplatin in cancer patients.