<p><i>Staphylococcus aureus</i> is a common colonizer of human skin, which, despite its ubiquitous nature, has a high virulence potential. Tolerating microbes in health but responding effectively to pathogens presents a challenge to the barrier tissues. Here, we examined the interaction of <i>S. aureus</i> with skin keratinocytes to study this early step of pathogenesis and pathogen discrimination. During infection, the <i>S. aureus</i> protease Staphopain A (ScpA) cleaves inert Gasdermin A (GSDMA). This releases an active N-terminal fragment similar to that formed by host protease regulators of other gasdermins family members. The resulting cell death by pyroptosis allows keratinocytes to deprive invasive <i>S. aureus</i> of an intracellular niche. These data support a model of GSDMA as an autonomous sensor of pathogenicity, in contrast to the conventional regulation of other gasdermins, which have dedicated host cell pathways. Gasdermins abundant in other tissues may have similar functions in host defense for the threat assessment of a microbe.</p>