The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health . SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme (ACE2) 1,2, and infection can result in pneumonia and acute respiratory dist ress syndrome . Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection 3 . Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication 4 and elevated inflammatory responses leading to more severe bronchitis 5,6, highlighting the impact of circadian pathways in respiratory function . We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication . Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system . Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19.