Preeclampsia is a hypertensive disorder of pregnancy associated with elevated levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and reduced nitric oxide (NO) bioavailability. Esomeprazole (ESO), a proton pump inhibitor (PPI) considered safe during pregnancy, has been proposed to reduce sFlt-1 levels in vitro. This study evaluated the effects of ESO in pregnant rats subjected to reduced uterine perfusion pressure (RUPP), a well-established model of preeclampsia. Pregnant rats received saline (Preg) or ESO (Preg+ESO), while RUPP-operated rats received saline (RUPP) or ESO (RUPP+ESO). At gestational day 21, maternal blood pressure was elevated in the Preg+ESO, RUPP, and RUPP+ESO groups compared with Preg, and ESO did not attenuate RUPP-induced hypertension. Fetal and placental weights were reduced in the RUPP group, whereas ESO increased placental weight in Preg+ESO and RUPP+ESO groups. Gastric pH was elevated by ESO, confirming reduced gastric acidity. Plasma sFlt-1 levels were increased in RUPP and significantly reduced by ESO in RUPP+ESO rats. NO metabolites (NOx) were decreased in RUPP but were unaffected by treatment. Endothelium-dependent relaxation was impaired in the RUPP and RUPP+ESO groups. In conclusion, ESO did not prevent hypertension or endothelial dysfunction, but reduced circulating sFlt-1, suggesting a partial modulatory effect on angiogenic imbalance in experimental preeclampsia.