Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. There have been no material advances in the treatment of preeclampsia for nearly 50 years. Combining in vitro studies and a clinical trial, we aimed to determine whether melatonin could be a useful adjuvant therapy. In a xanthine/xanthine oxidase (X/XO) placental explant model, melatonin reduced oxidative stress (8-isoprostane) and enhanced antioxidant markers (Nrf2 translocation, HO-1), but did not affect explant production of anti-angiogenic factors (sFlt, sEng, activin A). In cultured HUVECs, melatonin mitigated TNFα-induced vascular cell adhesion molecule expression and rescued the subsequent disruption to endothelial monolayer integrity but did not affect other markers for endothelial activation and dysfunction. In a phase I trial of melatonin in 20 women with preeclampsia, we assessed the safety and efficacy of melatonin on (i) preeclampsia progression, (ii) clinical outcomes, and (iii) oxidative stress, matching outcomes with recent historical controls receiving similar care. Melatonin therapy was safe for mothers and their fetuses. Compared to controls, melatonin administration extended the mean ± SEM diagnosis to delivery interval by 6 ± 2.3 days reduced the need for increasing antihypertensive medication on days 3-4 (13% vs 71%), days 6-7 (8% vs 51%), and at delivery (26% vs 75%). All other clinical and biochemical measures of disease severity were unaffected by melatonin. We have shown that melatonin has the potential to mitigate maternal endothelial pro-oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia.