Prenatal exposure to inorganic arsenic (iAs) has been associated with adverse developmental and reproductive outcomes. These outcomes may be tied to altered functionality of nuclear transcription factors such as the glucocorticoid receptor (GR) in the placenta and associated gene expression. The GR pathway is integral for proper fetal and placental development, and perturbations in this pathway may underlie observed associations between prenatal iAs exposure and adverse birth outcomes. We therefore set out to investigate whether iAs modulates the GR signaling pathway in placental cells. JEG-3 trophoblasts were exposed to environmentally-relevant doses of iAs, and mRNA expression assessed. To examine the links between iAs exposure, the GR signaling pathway, and epigenetic modification, DNA methylation levels were also quantified. Treatment with iAs altered the expression of 12 GR-genes that play a role in fetal and placental development. Furthermore, at a gene-specific level, mRNA abundance was associated with changes in DNA methylation patterning in JEG-3 cells, suggesting that the effects of iAs are mediated by epigenetic mechanisms. The identified target genes have been associated with prenatal iAs exposure, placental physiology, and fetal development. This study provides further evidence for iAs as an endocrine disruptor and provides insight as to the mechanisms by which prenatal iAs exposure may induce adverse birth outcomes.