Axon degeneration is the pivotal pathological event of acute traumatic neural injury as well as many chronic neurodegenerative diseases. It is an active cellular program and yet molecularly distinct from cell death. Much effort is devoted toward understanding the nature of axon degeneration and promoting axon regeneration. However, the fundamental mechanisms of self-destruction of damaged axons remain unclear, and there are still few treatments for traumatic brain injury (TBI) or spinal cord injury (SCI). Genetically approachable model organisms such as Drosophila melanogaster, the fruit fly, have proven exceptionally successful in modeling human neurodegenerative diseases. More recently, this success has been extended into the field of acute axon injury and regeneration. In this review, we discuss recent findings, focusing on how these models hold promise for accelerating mechanistic insight into axon injury and identifying potential therapeutic targets for TBI and SCI.