Caspases are increasingly recognised for their non-apoptotic roles in cellular differentiation and homeostasis, yet the molecular substrates mediating these functions remain largely unknown. Addressing this gap is critical to understanding caspase involvement in fundamental cell processes, disease mechanisms, and therapeutic potential. Here, we performed an unbiased mass spectrometry screen, complemented by biochemical, computational, genetic, and physiological analyses, to identify novel substrates of the Drosophila initiator caspase Dronc. Our approach revealed the kinesin motor protein Unc-104/KIF1A as a direct Dronc substrate and mapped its cleavage motif. We further demonstrate that Dronc-mediated cleavage of Unc-104/KIF1A prevents its pathological aggregation in vivo, thereby preserving axonal cargo transport, neuromuscular junction integrity, and motor function. This caspase-dependent proteostatic surveillance mechanism uncovers a previously unrecognised role for caspases in neuronal homeostasis and offers potential new insights into the molecular pathogenesis of KIF1A-associated neurological disorders (KANDs).