Group A Streptococcus (GAS) is a bacterial pathogen that causes a multitude of human diseases from impetigo and pharyngitis to severe infections such as toxic shock syndrome, rheumatic fever, and necrotizing fasciitis. One of the primary virulence factors produced by GAS is the peptide toxin Streptolysin S (SLS). In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS influences host cell signaling pathways at sub-lytic concentrations during infection. To expand upon these findings, we employed an antibody array-based approach to comprehensively identify global changes in host keratinocyte signaling in response to the SLS toxin. Through this study and subsequent biochemical analyses, we uncovered an SLS-dependent mechanism of host cytotoxicity in GAS-infected keratinocytes involving the inactivation of the cytoprotective factor Akt and subsequent activation of the p38 Mitogen Activated Protein Kinase (MAPK) cascade. Activation of this pathway promotes inflammatory signaling via Nuclear Factor kappa B (NFκB) activation and drives SLS-dependent programmed necrosis in keratinocytes.To further elucidate the effects of SLS-mediated inflammatory signaling in epithelial keratinocytes, we performed cytokine array studies to identify inflammatory cytokines that are produced by keratinocytes in response to GAS infection. These and subsequent analyses allowed for the identification of a robust, SLS-dependent increase in Interleukin 1-beta (IL-1β) production downstream of the p38 MAPK/NFκB signaling cascade. To address the physiological impact of increased IL-1β production, we performed in vitro studies in human keratinocytes as well as in vivo assessments in a humanized mouse model of GAS subcutaneous infection. These studies revealed that the SLS-mediated increase in IL-1β production leads to increased cytotoxicity in vitro as well as accelerated wound formation in vivo. In light of these findings, we propose that the production of SLS by GAS during skin infection promotes invasive outcomes by triggering programmed necrosis and inflammatory cascades in host cells to breach the keratinocyte barrier for dissemination into deeper tissues. Furthermore, our studies provide evidence that therapeutic targeting of this inflammatory signaling cascade may be a useful strategy to reduce SLS-mediated cell death and tissue destruction during the early stages of invasive GAS skin infection.