Group A Streptococcus (GAS) isolates with spontaneous mutations in covR and covS are frequently identified in patients with necrotizing fasciitis and toxic shock syndrome. CovR/CovS is a two-component regulator system, and the phosphorylation of CovR is solely modulated by CovS. Nonetheless, the phenotype of the ∆covS mutant and the ∆covR mutant is not entirely identical. It has been shown that the expression of SpeB protease is only detected in the ∆covR mutant, and the ∆covR mutant causes more severe local lesions than the ∆covS mutant in the mouse infection model. SpeB-mediated gasdermin A cleavage triggers keratinocyte death, resulting in sizeable lesion size but preventing invasive skin infection by GAS. This study, therefore, elucidated whether SpeB is a key factor related to trigger keratinocyte death after the ∆covR mutant infection. Although the ∆covR mutant caused more keratinocyte deaths than the ∆covS mutant, this difference was not contributed by SpeB but mediated by streptolysin S (SLS). Moreover, SLS in the ∆covR mutant contributed to increased macrophage cell death and elevated IL-1β levels. Similar to the SpeB expression profile, SLS was upregulated in the ∆covR mutant but repressed in the ∆covS mutant. In a mouse subcutaneous infection model, the SLS-deficient ∆covR mutant exhibited reduced lesion size and mortality compared to the ∆covR mutant, suggesting that SLS repression does not contribute to GAS immune evasion or invasive skin infection. This finding may help explain the differential presentations after ∆covR mutant and ∆covS mutant infection and why clinical GAS isolates more frequently harbor spontaneous mutations in covS rather than in covR.