Background: Cochlear cell apoptosis is an important factor influencing presbycusis. Estrogen has a protective effect on hearing, but the specific mechanism of its protective effect on presbycusis is not clear. We studied whether estrogen affects apoptosis by regulating TMEM16A, thus preventing presbycusis. Methods: In an animal model, the hearing threshold was detected by auditory brainstem response (ABR). HE and transmission electron microscopy was used to observe morphological changes. qRT-PCR was used to analyze mRNA level changes. In experiments with cells, primary culture and identification of PCs in the cochlear stria vascularis (SV) were performed. The expression of TMEM16A was detected by immunofluorescence, and the apoptosis rate was detected by flow cytometry. Results: The results showed that estrogen intervention could improve presbycusis, cochlear SV atrophy and PCs degeneration in aged mice, and it could reduce expression of TMEM16A and apoptosis. In addition, experiments with cells showed that TMEM16A expression and apoptosis were increased in the aging cell group, but these effects were reversed by estrogen or T16Ainh-A01 intervention.Conclusions: These results show that estrogen might reduce the apoptosis of PCs by downregulating TMEM16A, which would then protect against hearing loss via presbycusis. This study may provide a novel potential treatment and prevention method for presbycusis.* Xuerui Li and Yang Zhang contributed equally to this work.