Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non‐pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two‐compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9–61.6%) lower compared to non‐pregnant, most likely due to inhibition of CYP2C19. In non‐pregnant participants after repeated dosing, clearance was 54.9% (48.2–63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0–52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non‐pregnant individuals, since CYP2C19 is already inhibited due to pregnancy.