Pregnant women may be prescribed opioid drugs for pain or may abuse these drugs. The placenta may be key to understanding how opioids cause adverse pregnancy outcomes. Maternal oxycodone (OXY) exposure of pregnant mice leads to disturbances in the layer of invasive parietal trophoblast giant cells (pTGC) that forms the interface between the placenta and uterus and is analogous to extravillous trophoblasts of the human placenta. These cells are probably crucial to coordinating the metabolic needs of the conceptus with those of the mother and are also primary participants in the placenta-brain axis. Their large nuclear size, however, has precluded both single cell (sc) and single nucleus (sn) RNA-seq analyses beyond embryonic day (E) 8.5. Here we compared the transcriptomes of placentas from pregnant mice exposed to OXY with unexposed controls at E12.5, with particular emphasis on the pTGC. The non-fluidic Parse snRNA-seq approach permitted characterization of the nuclear transcriptomes of the major placental cell lineages and their presumed progenitors at E12.5. OXY exposure had negligible effect on components of the placental labyrinth, including the two syncytial cell layers, but caused transcriptomic changes consistent with metabolic stress throughout the spongiotrophoblast. Most notably, there was loss of the majority of pTGCs, whose normal gene expression is consistent with elevated energy demand relating to biosynthesis of multiple secretory products, especially hormones, and endoduplication of DNA. This unusual sensitivity of pTGC may put the pregnancy and future health of the offspring at particular risk to OXY exposure.