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COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment and one important factor to consider is oxygen tension, where hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via a HIF-1α dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication showing that post-entry steps in the viral life cycle are oxygen-sensitive. This study highlights the importance of HIF signalling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19., Graphical Abstract, Wing et al. demonstrate that key aspects of the SARS-CoV-2 life cycle are dependent on cellular oxygen tension. Activation of the cellular oxygen sensing pathway inhibits SARS-CoV-2 infection, highlighting a key cellular pathway that could be exploited as a potential therapeutic avenue for COVID-19.