COVID-19 can lead to heart failure (HF) and even cardiac death. The 2’,5’-oligoadenylate synthetase (OAS) gene family is associated with the antiviral immune responses of COVID-19. While the potential association of OAS family with cardiac injury and failure in COVID-19 has not been determined. Hence, in our study, the expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. miRNAs targeting OAS gene family were explored from Targetscan and HF miRNA database. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database. Results showed that OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expression genes (DEGs) in two datasets were enriched in cardiovascular disease and COVID-19 related pathways, respectively. The miRNAs-target analysis indicated that 10 miRNAs increase OAS genes expression. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family, especially estradiol. In conclusion, OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19.