SARS-CoV-2 primarily infects the respiratory tract, but cardiovascular, renal, digestive, and neurological complications are also reported in severe COVID-19. To investigate the molecular mechanisms of infection in these organs, we conducted a series of comparative analysis of transcriptional changes following infection in human stem cell derived lung, and heart tissues. We observed variable levels of infection efficacy and in particular, lung and heart tissues showed differential interferon signalling in response to infection. Our identification of these responses reveals a need for parallel evaluation in drug therapy to appropriately evaluate and identify drug targets and candidates.