In this work, we investigated the effects of USP5 on EphA2 protein stability and NPC cell radiosensitivity, and found that USP5 interacted with EphA2 and decreased its ubiquitination, thereby stabilizing EphA2 in NPC cells, USP5 promoted in vitro and in vivo NPC cell radioresistance via stabilizing EphA2, and MBZ reduced in vitro and in vivo NPC cell radioresistance by targeting USP5/EphA2 axis. This evidence concerns the gene EPHA2 and nasopharyngeal carcinoma.