Injured axons undergo a controlled, self-destruction process, known as Wallerian degeneration. However, the underlying mechanism remains elusive. Using the Drosophila wing nerve as a model, we identify the ESCRT component Vps4 as a previously unidentified essential gene for axonal integrity. Up-regulation of Vps4 remarkably delays degeneration of injured axons. We further reveal that Vps4 is required and sufficient to promote autophagic flux in axons and mammalian cells. Moreover, using both in vitro and in vivo models, we show that the function of Vps4 in maintaining axonal autophagy and suppressing Wallerian degeneration is conserved in mammals. Last, we uncover that Vps4 protein is rapidly depleted in injured mouse axons, which may underlie the injury-induced autophagic impediment and the subsequent axonal degeneration. Together, Vps4 and ESCRT may represent a novel signal transduction mechanism in axon injury and Wallerian degeneration.