In the face of acute or chronic axonal damage, neurons and their axons undergo a number of molecular, cellular, and morphological changes. These changes facilitate two types of responses, axonal degeneration and regeneration, both of which are remarkably conserved in both vertebrates and invertebrates. Invertebrate model organisms, including Drosophila and C. elegans, have offered a powerful platform with accessible genetic tools for manipulation and amenable nervous system for visualization. Thus far, several critical components and pathways in axonal degeneration and regeneration have been identified in invertebrate studies, including Sarm and Wallenda/DLK. This article highlights important findings in Drosophila, C. elegans, and other invertebrate injury models that have shed light upon the mechanism in axonal injury response.