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Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin–Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7−/− mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection. Schematic of the role of P2X7 receptor in neomycin-induced HC loss. Under physiological control conditions, P2X7 receptor acts as a channel. ATP and small molecules can pass through it, while large molecules cannot. After neomycin exposure, large amounts of ATP are released from cells and the extracellular concentration of ATP increases rapidly. In addition, more P2X7 receptors are synthesized and appear in the membrane. The high concentrations of ATP cause P2X7 receptor to open as a pore that is large enough for neomycin to enter the HCs, thus damaging the HCs and causing apoptosis. [Display omitted] • AGAs induced cochlear HC damage is associated with changes in eATP concentration and P2X7 receptor activation. • P2X7 receptor is involved to AGAs uptake in HCs. • AGAs-related mitochondria-mediated oxidative stress could be abolished by deleting P2rx7. • P2X7 receptor might be a new target for HC protection from AGAs. [ABSTRACT FROM AUTHOR]