The mechanisms underlying neuronal outgrowth after injury are poorly understood. In a Drosophila model of neuronal injury, knockout of the gene encoding the fly mechanosensitive ion channel Piezo (DmPiezo) in non-regenerating neurons resulted in substantial axon regrowth not observed in wild-type flies. In a mouse sensory neuron injury model (corneal sensory nerve laser ablation), conditional knockout of the gene encoding PIEZO1 (the mammalian homologue of DmPiezo) drove a relative increase in axon regeneration compared with controls. Thus, PIEZO channels may have an evolutionarily conserved role in inhibiting axon regeneration.