Currently authorized direct-acting antivirals for the treatment of SARS-CoV-2 infection, which target the viral polymerase and viral protease, have been associated with viral resistance and variable efficacy. Given the potentially higher barrier to drug resistance, as well as increased breadth of activity across coronavirus variants and species, host-directed therapeutics represent an attractive alternative approach. Here, Wei et al. demonstrate in vitro that a mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodelling complex, BRG1/BRM-associated factor (cBAF), is essential for SARS-CoV-2 entry into cells, and entry requires the catalytic activity of the ATPase subunit SMARCA4. Mechanistically, mSWI/SNF complex catalytic activity was shown to be essential for DNA accessibility at the angiotensin-converting enzyme 2 (ACE2) locus. Furthermore, the transcription factors HNF1A/B were demonstrated to bind to and direct cBAF complexes to sites of high HNF1A/B motif density at the ACE2 locus, to regulate ACE2 expression. In cell lines and primary human cell types — including human bronchial epithelial cells — inhibiting mSWI/SNF ATP-dependent chromatin remodelling activity using three different orally bioavailable SMARCA4/2-specific small-molecule inhibitors and degraders attenuated ACE2 expression, preventing infection with diverse SARS-CoV-2 variants and a remdesivir-resistant mutant virus.