Recent progress has been made regarding the prevention of hearing loss. However, the complete protection of both hair cells and spiral ganglion neurons, with restored function, has not yet been achieved. It has been shown that spiral ganglion neuronal loss can be prevented by neurotrophin 3 (NT3) and hair cell damage by N-methyl-D-aspartate (NMDA) receptor antagonists. Here we demonstrate that the combined treatment with MK801, a NMDA antagonist, and NT3 protect both cochlear morphology and physiology from injury. Pretreatment with MK801 prevented hearing loss and the dendrites of the spiral ganglion neurons from swelling after noise-induced damage. The acute phase of insult with the aminoglycoside antibiotic amikacin resulted in swollen afferent dendrites beneath the inner hair cells. The chronic phase resulted in complete hair cell loss and near-complete loss of spiral ganglion neurons. This damage caused a near-complete loss of hearing sensitivity as displayed by elevated (>90-dB sound pressure levels) auditory brainstem response thresholds. The treatment of amikacin-exposed animals with MK801 gave only a partial protection of hearing. However, the combined treatment with NT3 and MK801 in the amikacin-comprised ear resulted in improved mean hearing within 20 dB of normal. Furthermore, hair cell loss was prevented in these animals and spiral ganglion neurons were completely protected. These results suggest that the NMDA antagonist MK801 protects against noise-induced excitotoxicity in the cochlea whereas the combined treatment of NT3 and MK801 has a potent effect on preserving both auditory physiology and morphology against aminoglycoside toxicity.