HuR is a widely expressed RNA binding protein that interacts with specific AU‐rich domains in target mRNAs and regulates their expression by modulating stability and/or translation. RNA binding proteins such as HuR are becoming recognized as potential mediators of cardiac physiology and pathology but the role of HuR in cardiac hypertrophy is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes and is necessary for hypertrophic cell growth. Using an inducible cardiomyocyte‐specific HuR deletion mouse (iCM‐HuR−/−), we have shown that cardiac specific deletion of HuR significantly reduces hypertrophy compared to wild‐type mice at 8 weeks post‐transverse aortic constriction (TAC). More importantly, the iCM‐HuR−/− mice exhibited significantly preserved ejection fraction, reduced chamber dilation, and less fibrosis compared to WT at 8 weeks post‐TAC. To elucidate the downstream target genes of of HuR in the heart and identify potential mechanisms by which HuR deletion reduces pathological cardiac hypertrophy, we used RNA‐seq to identify HuR‐dependent gene expression in the setting of cardiac hypertrophy. Using the NIH DAVID Functional Annotation Tool, our results indicate a significant increase in genes promoting anti‐apoptotic Akt signaling in hearts from iCM‐HuR−/− mice following TAC. However, since HuR binding typically stabilizes target mRNA, we observed a much larger number of significantly down‐regulated mRNA transcripts in iCM‐HuR−/− mice. Among these were genes involved in key cellular growth processes such as muscle cell differentiation, cell proliferation, cell cycle, and positive regulation of transcription. Thus, our results suggest that HuR deletion protects the heart from pathological cardiac hypertrophy by promoting pro‐survival Akt signaling while decreasing the expression of genes involved in cell growth and differentiation.Support or Funding InformationThis work was partially funded by an American Heart Association Scientist Development Grant and NIH R01 HL132111 (MT).