Based on zinc oxysulfides, quaternary semiconductors MZnOS (M = Ca, Ba, Sr, or other metals) are gaining attention as host materials for luminescent dopant ions. While these materials have been applied in various piezoluminescent devices, their biocompatibility has been scarcely investigated. In this study, yellow-to-red emitting triboluminescent powders of Mn 2+-doped CaZnOS and BaZnOS (CaZnOS:Mn 2+ and BaZnOS:Mn 2+) were synthesized via solid-state reaction. They were studied with a focus on their optical properties and, critically, biocompatibility. Both compounds exhibit photoluminescence (PL) and mechanoluminescence (ML) emissions of Mn 2+ ions, characterized by a single broad band spanning 550–700   nm. The PL emission peaks at 587   nm (yellow light) of CaZnOS:Mn 2+ and 623   nm (red light) of BaZnOS:Mn 2+, irrespective of excitation wavelength. Conversely, the ML emission for both materials peaks at 592   nm, with the intensity of CaZnOS:Mn 2+ significantly exceeding that of BaZnOS:Mn 2+. Subsequently, a flexible tactile film was fabricated, and obtaining ML images underscores their considerable potential for application in tactile sensing and wearable devices. Finally, both compounds were assayed for cytocompatibility and biocompatibility, exhibiting very low cytotoxicity in vitro to mouse brain neurons and microglia cells and demonstrating satisfactory compatibility with mouse skin in vivo. These findings indicate that MZnOS:Mn 2+ (M = Ca, Ba) possess a promising combination of functional luminescent behavior and biocompatibility, positioning them as highly promising candidates for future applications in tactile imaging, artificial electronic skin, mechanoresponsive drug delivery, and real-time stress sensing.