Objective A C57BL/6 mouse chronic unpredictable mild stress model of depression was establishedto investigate the effect of high frequency sound waves in Mozart’s K448 Sonata on depression. Methods Establishment ofa chronic stress model: Mice were divided into a blank group (n = 10) lived with no stress and model group (n = 36)established 5 weeks of chronic mild and unpredictable stimulation (CUMS). Therapeutic intervention: The mice in themodel group were randomly divided into the model control group (n =12), fluoxetine group (n =12), and music group (n= 12) after 5 weeks. Fluoxetine hydrochloride solution (10 mg/ kg) was injected intraperitoneally every day in thefluoxetine group, and the other two groups were injected with the same amount of saline lasted 2 weeks. The music groupreceived a 2-hour high frequency music intervention every day lasted 2 weeks, while the other two groups did not. Outcomevariables: Weight was recorded 3 days before the experiment and every week during the experiment. Tail suspension test(TST) and forced swimming test (FST) were performed in weeks 1, 5, and 7. At the end of week 7, mice were sacrificedand brain homogenates were prepared. BDNF levels were determined using an enzyme-linked immunosorbent assay(ELISA). Results At week 5, in the TST, immobility times of the model group were significantly longer than that of theblank group ( P < 0. 01). In the FST, immobility times of the model group were longer than that of the blank group ( P <0. 05). Compared with the model control group, both the fluoxetine group and music group exhibited a significantly shorterimmobility time of tail suspension ( P < 0. 01, P < 0. 05) Compared with the blank group, the model control group had asignificant lower BDNF content in brain homogenates ( P < 0. 01); compared with the model control group, the fluoxetinegroup had a significantly higher BDNF content ( P < 0. 01), and there was no significant difference in BDNF contentbetween the music group and the model control group ( P > 0. 05). Conclusion Mozart K448 Sonata high frequency sound waves may optimise the therapeutic effect on depression mice models.