Background: Susceptibility to noise varies dramatically between mice of the same genetic background; however, the underlying molecular mechanism remains unknown. Methods: C57BL/6J (B6) mice of the same sex, age, and strain were exposed to noise of the same intensity and duration, and the auditory brainstem response (ABR) threshold was determined 48 h later. Some mice had significant hearing loss, while some did not; the ABR threshold measured in these two groups of mice was significantly different. The cochlea of the two groups of mice was dissected, and RNA sequencing and analysis were performed. Differentially expressed genes (DEGs) between the two groups were selected, Kyoto Encyclopedia of Genes and Genomes pathway analysis was performed, and proteinprotein interaction network maps were listed. Results: This study showed that noise exposure of the same intensity and duration caused different degrees of hearing loss in C57BL/6J (B6) mice. This was the result of the up-regulation or down-regulation of many genes, such as Nop2, Bysl, Rrp9, Spsb1, Fbxl20, and Fbxo31. Changes in the transcriptome of these genes may affect cochlear susceptibility to noise. Conclusion: The DEGs identified in this experiment may provide more insight into protocols for gene therapy in the clinical practice of hearing loss.