The RNA-binding protein human antigen R (HuR) has been shown to reduce cardiac remodeling following both myocardial infarction and cardiac pressure overload, but the full extent of the HuR-dependent mechanisms within cells of the myocardium has yet to be elucidated. Wild-type mice were subjected to 30 min of cardiac ischemia (via LAD occlusion) and treated with a novel small molecule inhibitor of HuR at the time of reperfusion, followed by direct in vivo assessment of cardiac structure and function. Direct assessment of HuR-dependent mechanisms was done in vitro using neonatal rat ventricular myocytes (NRVMs) and bone marrow-derived macrophages (BMDMs). HuR activity is increased within 2 h after ischemia/reperfusion (I/R) and is necessary for early post-I/R inflammatory gene expression in the myocardium. Despite an early reduction in inflammatory gene expression, HuR inhibition has no effect on initial infarct size at 24 h post-I/R. However, pathological remodeling is reduced with preserved cardiac function at 2 weeks post-I/R upon HuR inhibition. RNA sequencing analysis of gene expression in NRVMs treated with LPS to model damage-associated molecular pattern (DAMP)-mediated activation of toll-like receptors (TLRs) demonstrates a HuR-dependent regulation of pro-inflammatory chemokine and cytokine gene expression in cardiomyocytes. Importantly, we show that conditioned media transfer from NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory gene expression and M1-like polarization in bone marrow-derived macrophages (BMDMs) compared to NRVMs treated with LPS alone. Functionally, HuR inhibition reduces macrophage infiltration to the post-ischemic myocardium in vivo. Additionally, we show that LPS-treated NRVMs induce the migration of peripheral blood monocytes in a HuR-dependent endocrine manner. These studies demonstrate that HuR is necessary for early pro-inflammatory gene expression in cardiomyocytes following I/R injury that subsequently mediates monocyte recruitment and macrophage activation in the post-ischemic myocardium.