Group A Streptococcus (GAS) is a leading human pathogen commonly associated with pharyngitis (“strep throat”) but also capable on occasion of producing severe, invasive diseases including necrotizing fasciitis (“flesh-eating disease”) and toxic shock syndrome, even in previously healthy individuals. GAS systemic disease reflects a large suite of virulence factors that enable the pathogen to avoid eradication by phagocytic defenses of the host immune system. In our studies of the globally-disseminated hyperinvasive GAS M1T1 clone, we have elucidated novel functions of several classical GAS virulence factors in modulating host immunity. The cell-wall anchored M1 protein, the most abundant and immunodominant antigen on the GAS surface, is known for its fibrinogen-binding and antiphagocytic properties. We find that the hypervariable N-terminal domain can sequester cationic cathelicidin antimicrobial peptides and histones to promote GAS resistance to killing by neutrophils and neutrophil extracellular traps. M protein also activates the NLRP3 inflammasome triggering rapid pyroptotic cell death. The GAS hyaluronic acid (HA) capsule is upregulated during systemic infection, and mimics a common host glycosaminoglycan to cloak opsonic targets on the bacterial surface. We reveal that GAS uses HA to engage an inhibitory Siglec receptor on the neutrophil cell surface, blunting neutrophil activation and promoting pathogen survival. Finally, the broad-spectrum GAS cysteine protease SpeB degrades host defense molecules such as antimicrobial peptides and immunoglobulins, but is paradoxically inactivated during invasive disease pathogenesis. We describe an caspase- and inflammasome-independent IL-1β signaling pathway to detect bacterial proteases that is critical in host defense against GAS. This pathway may explain an unusually high rate of severe GAS infection in patients receiving IL-1β receptor blocker therapy.