We studied the effect of KDM5 family demethylase inhibitors (JIB-04, PBIT, and KDOAM-25) on the penetration of SARS-CoV-2 pseudotyped viruses into differentiated Caco-2 cells and HEK293T cells with ACE2 hyperexpression. The above drugs were not cytotoxic. Only KDOAM-25 significantly reduced virus entry into the cells. The expression of ACE2 mRNA in Caco-2 significantly increased, while TMPRSS2 expression did not significantly change under these conditions. In differentiated Caco-2 cells, KDOAM-25 did not affect the expression of BRCA1, CDH1, TP53, SNAI1, VIM, and UGCG genes, for which an association with knockdown or overexpression of KDM5 demethylases or with the action of demethylase inhibitors had previously been shown. In undifferentiated Caco-2 cells, the expression of BRCA1, SNAI1, VIM, and CDH1 was significantly increased under the action of KDOAM-25.