The USA300 strains of Staphylococcus aureus are the major cause of skin and soft tissue infection in the United States. Invasive USA300 infection has been attributed to several virulence factors, including protein A and the α-hemolysin (Hla), which cause pathology by activating host signaling cascades. Here we show that S. aureus exploits the proinflammatory bias of human keratinocytes to activate pyroptosis, a caspase 1-dependent form of inflammatory cell death, which was required for staphylococci to penetrate across a keratinocyte barrier. Keratinocyte necrosis was mediated by calpains, Ca(2+)-dependent intracellular proteases whose endogenous inhibitor, calpastatin, is targeted by Hla-induced caspase 1. Neither Panton-Valentine leukocidin nor protein A expression was essential, but inhibition of either calpain or caspase 1 activity was sufficient to prevent staphylococcal invasion across the keratinocytes. These studies suggest that pharmacological interruption of specific keratinocyte signaling cascades as well as targeting the Hla might prevent invasive skin infection by staphylococci.