AbstractPreeclampsia (PE) is a serious hypertensive complication of pregnancy and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity, including establishment of long‐term complications. The continued prevalence of PE stresses the need for identification of novel treatments which can target prohypertensive factors implicated in the disease pathophysiology, such as soluble fms‐like tyrosine kinase 1 (sFlt‐1). We set out to identify novel compounds to reduce placental sFlt‐1 and determine whether this occurs via hypoxia‐inducible factor (HIF)‐1α inhibition. We utilized a commercially available library of natural compounds to assess their ability to reduce sFlt‐1 release from primary human placental cytotrophoblast cells (CTBs). Human placental explants from normotensive (NT) and preeclamptic (PE) pregnancies were treated with varying concentrations of luteolin. Protein and mRNA expression of sFlt‐1 and upstream mediators were evaluated using ELISA, western blot, and real‐time PCR. Of the natural compounds examined, luteolin showed the most potent inhibition of sFlt‐1 release, with >95% reduction compared to vehicle‐treated. Luteolin significantly inhibited sFlt‐1 in cultured placental explants compared to vehicle‐treated in a dose‐ and time‐dependent manner. Additionally, significant decreases in HIF‐1α expression were observed in luteolin‐treated explants, suggesting a mechanism for sFlt‐1 downregulation. The ability of luteolin to inhibit HIF‐1α may be mediated through the Akt pathway, as inhibitors to Akt and its upstream regulator phosphatidylinositol‐3 kinase (PI3K) resulted in significant HIF‐1α reduction. Luteolin reduces anti‐angiogenic sFlt‐1 through inhibition of HIF‐1α, making it a novel candidate for the treatment of PE.