Small extracellular vesicles (sEVs) play an important role in intercellular communication as well as pathological development. Here, to explore the roles of sEVs in the progression of cisplatin-induced ototoxicity, we isolated sEVs from the conditioned culture medium of cisplatin-induced cochlear explants (Cis-sEVs) and the control group (Ctrl-sEVs) and profiled their cargos using label-free LC-MS/MS. Numerous proteins involved in the regulation of the damage response were enriched in the Cis-sEVs. Cltc, Cct2, and Hspa8, which are potentially involved in protein homeostasis and autophagy, are up-regulated in Cis-sEVs compared to Ctrl-sEVs but not in cisplatin-damaged cochlear tissue or in HEI-OC1 cell lysates.