The aim of this study was to investigate the mechanisms of diet-induced obesity on hearing degeneration in CD/1 mice. Sixty 4-week-old male CD/1 mice were randomly and equally divided into 2 groups. For 16 weeks, the diet-induced obesity (DIO) group was fed a high fat diet and the control group was fed a standard diet of 13.43 % kcal fat. The morphometry, biochemistry, auditory brainstem response thresholds, omental fat, and histopathology of the cochlea were compared between the beginning and end of the study (4 vs. 20 weeks old). The results show that the body weight, fasting plasma triglyceride concentrations, and omental fat weight were higher in the DIO group than in the control group at the end of experiment. The auditory brainstem response thresholds at high frequencies were significantly elevated in the DIO group compared to those of the control group. Histology studies showed that, compared to the control group, the DIO group had blood vessels with smaller diameters and thicker walls in the stria vascularis at the middle and basal turns of the cochlea. The cell densities in the spiral ganglion and spiral ligament at the basal turn of the cochlea were significantly lower in the DIO group. Immunohistochemical staining showed that hypoxia-induced factor 1 (HIF-1), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), caspase 3, poly(ADP-ribose) polymerase-1, and apoptosis inducing factor were all significantly more dense in the spiral ganglion and spiral ligament at the basal turn of cochlea in the DIO group. Our results suggest that diet-induced obesity exacerbates hearing degeneration via increased hypoxia, inflammatory responses, and cell loss in the spiral ganglion and spiral ligament and is associated with the activation of both caspase-dependent and -independent apoptosis signaling pathways in CD/1 mice.