Introduction: Endocardial Fibroelastosis (EFE) is defined by fibrotic tissue on the endocardium, stunting cardiac development. EFE restricts compliance, leading to heart failure, and contributing to increased morbidity and mortality. While research suggests that EFE forms through aberrant endothelial-to-mesenchymal transition (EndoMT), the pathologic triggers are still speculative. Anecdotally, we observed EFE development in patients with abnormal left ventricular flow. Objective: Our objective is to study whether abnormal flow induces EndoMT in neonatal endocardium and promotes EFE development, and whether losartan treatment, which can decrease TGF-β production to impair EndoMT, can abrogate EFE formation. Methods and Results: Using a rodent model of EFE, we establish three flow conditions in neonatal hearts: Normal Flow (NF), Static/no flow (S), and Regurgitant Flow (RF). We demonstrate EFE development, increased mRNA and protein expression of EndoMT markers (αSMA, SNAIL), and EndoMT-related signaling pathways (TGFβ, NOTCH1) in S and RF, whereas NF conditions do not. Further, losartan treatment significantly decreases EFE in neonatal hearts and decreases mRNA and protein expression of EndoMT markers. Next, human endocardial endothelial cells were isolated from left ventricular tissue and subjected to two flow conditions: static and laminar shear stress (LSS). RNAseq analysis demonstrate that laminar shear stress suppresses the gene expression critical for mesenchymal differentiation and Notch signaling, which are associated with EndoMT progression. Conclusions: Our data demonstrate that the absence of normal flow can promote EFE development through EndoMT. We identify losartan as a potential therapy, as it is able to abrogate EFE development in our animal model.