Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide. We have previously reported that magnesium sulfate therapy is effective for early-onset (EO) preeclampsia. To investigate the molecular mechanisms underlying this favorable effect, metabolomics analysis of magnesium sulfate–treated preeclamptic placentas was performed using capillary electrophoresis time of flight mass spectrometry. There were significant metabolic differences between EO-preeclamptic placentas (n=7) and other placentas (late-onset preeclampsia [n=3], normal pregnancies [n=10]). In EO-preeclamptic placentas, the glutathione metabolism pathway was markedly upregulated, whereas single-sample gene-set enrichment analysis using a publicly available microarray dataset (GSE75010) showed that the glutathione metabolism pathway was significantly downregulated in EO-preeclamptic placentas compared with nonpreeclamptic controls. Metabolomic profiles showed that magnesium sulfate significantly promoted glutathione production in an immortalized trophoblast cell line under oxidative stress conditions but not under normal conditions. Magnesium sulfate suppressed hydrogen peroxide–induced production of reactive oxygen species. Exploratory analysis revealed that urinary 8-isoprostane was decreased in all 5 women treated with magnesium sulfate for preeclampsia with severe features. These findings suggest that magnesium sulfate is effective for treating EO-preeclampsia partly because of its antioxidant effects on trophoblasts.