Preeclampsia (PE) is a multifactorial disorder of pregnancy, characterized by new-onset gestational hypertension. High-throughput mRNA sequencing (RNA-seq) was performed to analyze the gene expression patterns in placentas from patients with early-onset PE (EOPE). PR domain zinc-finger protein 1 (PRDM1) expression increased in the chorionic villi and placental basal plate from patients with PE and nitro--arginine methyl ester (L-NAME)-treated rats. Inhibition of PRDM1 enhanced trophoblast/extravillous trophoblast (EVT) cell invasion/migration and reduced apoptosis under hypoxia/reoxygenation (H/R) conditions. RNA-seq data indicated that the expression of CREB-binding protein (CREBBP), a transcriptional coactivator, was upregulated in preeclamptic placentas and showed a positive correlation with that of PRDM1. Genetic and pharmacological inhibition of CREBBP exhibited anti-apoptotic and pro-invasive roles. H/R stimulation upregulated CREBBP expression and augmented the binding of PRDM1 to CREBBP's promoter. CREBBP was further validated as a direct downstream target of PRDM1. Collectively, our work reveals an involvement of the activated PRDM1-CREBBP axis in PE-associated trophoblast dysfunction.