RNA sequencing revealed upregulation of genes including Mal, Fos, Rapgef3, Papss2, Adamts4, and Heph, and downregulation of genes such as Pde5a, Kcnma1, Nr4a1, Dlgap3, Slc18a2, and Dgkg.<h4>Conclusion</h4>Fluoxetine exerted only modest, 4 kHz‐restricted improvements in ABR thresholds and did not restore cochlear structure or normal hearing following noise‐induced hearing loss. Here, PDE5A is linked to hearing loss disorder.