Group A Streptococcus (GAS) invades human cells, damages endosomal membranes via pore-forming toxins, and escapes into the cytoplasm. Cytoplasmic GAS is targeted by selective autophagy through the recruitment of ubiquitin and the cargo receptor p62. Meanwhile, p62, upon the activation of selective autophagy, binds to KEAP1, an oxidative stress sensor, leading to the activation of Nrf2 and the induction of host defense responses. We investigated the function of Nrf2 in GAS-infected human epithelial cells and found that IL-6 was activated in an Nrf2-dependent manner upon infection. However, Nrf2 nuclear translocation and IL-6 activation were independent of p62. Confocal microscopy of infected cells revealed that the phosphorylation of p62, which is crucial for KEAP1 binding, occurred only in the early stages of infection and gradually declined. Since p62 phosphorylation is regulated by mTOR and its upstream regulator AMPK, we focused on NADase, a secreted toxin of GAS, and analyzed its mutant strain. We showed that NADase-induced energy stress led to excessive activation of AMPK and inactivation of mTOR. These results suggest that NADase-mediated mTOR inactivation inhibits KEAP1 activation via p62.