The study identifies *Drosophila* TMEM63 (*DmTMEM63*) as a lysosomal mechanosensory ion channel, which localizes to lysosomes and mediates lysosomal mechanosensitivity. Endogenous *DmTMEM63* proteins are localized to lysosomes, and their absence in *Tmem63* mutant flies leads to impaired lysosomal degradation, synaptic loss, progressive motor deficits, and early death. The channel is permeable to Na^+^ and K^+^ ions and responds to hypo-osmotic stress, as evidenced by calcium signaling. *DmTMEM63* is essential for lysosomal morphology and function, and its overexpression or knockout affects lysosome positioning and shape. The evolutionary conservation of *TMEM63* homologues is demonstrated in mammalian cells, where *TMEM63A* mediates lysosomal mechanosensitivity. These findings reveal the role of *DmTMEM63* in lysosomal mechanotransduction and provide insights into the interplay between intracellular mechanotransduction, organellar dynamics, and related pathologies.The study identifies *Drosophila* TMEM63 (*DmTMEM63*) as a lysosomal mechanosensory ion channel, which localizes to lysosomes and mediates lysosomal mechanosensitivity. Endogenous *DmTMEM63* proteins are localized to lysosomes, and their absence in *Tmem63* mutant flies leads to impaired lysosomal degradation, synaptic loss, progressive motor deficits, and early death. The channel is permeable to Na^+^ and K^+^ ions and responds to hypo-osmotic stress, as evidenced by calcium signaling. *DmTMEM63* is essential for lysosomal morphology and function, and its overexpression or knockout affects lysosome positioning and shape. The evolutionary conservation of *TMEM63* homologues is demonstrated in mammalian cells, where *TMEM63A* mediates lysosomal mechanosensitivity. These findings reveal the role of *DmTMEM63* in lysosomal mechanotransduction and provide insights into the interplay between intracellular mechanotransduction, organellar dynamics, and related pathologies.