Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the road for future clinical trials.