Mechanosensation enables cells to detect physical forces, including membrane stretch, pressure, shear stress, and osmotic stress, and to convert them into biochemical and electrical signals that regulate cellular function. Among the emerging families of mechanosensitive proteins, TMEM63/OSCA channels have recently been recognized as evolutionarily conserved mechanically activated ion channels with important roles in cellular and organellar physiology. While mechanosensation has traditionally been studied at the plasma membrane, increasing evidence suggests that intracellular organelles also experience and respond to mechanical cues. Lysosomes are particularly exposed to membrane tension, curvature changes, osmotic fluctuations, and cytoskeletal forces generated during trafficking, fusion-fission dynamics and cargo loading. These observations support an emerging view of lysosomes as dynamic hubs of mechano-responsive signaling in addition to their established degradative functions. Recent studies have identified TMEM63 proteins at both the plasma membrane and lysosomes, where they are proposed to couple mechanical and osmotic stimuli to ion flux, membrane remodeling, and stress-adaptive signaling pathways. In this review, we summarize current advances in the structural biology, gating mechanisms, and physiological functions of TMEM63/OSCA channels with particular emphasis on their emerging roles in lysosomal mechanobiology. We further discuss evidence linking TMEM63/OSCA dysfunction to human channelopathies and highlight key questions regarding mechanosignaling across cellular compartments. By integrating recent findings from mechanobiology, organelle physiology, and disease genetics, this review positions TMEM63 channels as an important molecular link between membrane mechanics, lysosomal function, and cellular homeostasis.