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. Display omitted •Pro-inflammatory factors drive systolic and diastolic cardiac dysfunction•BRD4 activation drives diastolic dysfunction and is blocked by clinically relevant drugs•BET inhibition decreases ACE2 expression and decreases SARS-CoV2 infection COVID-19 causes cardiac injury, although mechanisms and effective therapeutics are lacking. In this study, Mills et al., show that cytokines elevated in COVID-19 patients drive cardiac dysfunction. These responses are mapped using phosphoproteomics and single nuclei RNA sequencing, enabling a targeted drug screen to identify therapeutics for rapid repurposing. BET inhibitors were identified as leading candidates to block cardiac dysfunction and decrease SARS-CoV-2 cardiac infection.