Our study demonstrates not only that SARS-CoV-2 reduces the expression of NRF2 in cells, but it also affects its biological transcriptional activity as the infection resulted in a significant decrease in the expression of a cluster of NRF2-dependent genes—SOD1, CAT, GPX1, GCLC, NQO1, and HMOX1—in human lung-derived epithelial cells. This evidence concerns the gene HMOX1 and infection.