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Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage., Competing Interests: Declaration of interests R.J.M., J.E.H., G.A.Q.-R., D.M.T., and E.R.P. are co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. R.J.M., E.R.P., D.M.T., B.G., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. D.M.T. and B.G. are employees of Dynomics. C.H., D.G., L.F., J.J., M.S., N.C.W.W., and E.K. are employees of Resverlogix. S.J.N. received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute filed a patent on the use of BETi., (Copyright © 2021 Elsevier Inc. All rights reserved.)