The rising prevalence of opioid use during pregnancy poses serious public health concerns, yet the molecular mechanisms by which opioids such as oxycodone impact fetal development remain poorly understood. This study investigates the effects of chronic perinatal oxycodone exposure on the composition and signaling functions of placenta-derived extracellular vesicles (EVs) using a rat model. EVs were isolated and characterized via nanoparticle tracking analysis, transmission electron microscopy, Western blotting, and label-free quantitative proteomics. Bioinformatic enrichment analyses revealed that oxycodone exposure significantly altered EV biophysical properties and protein cargo, with pronounced downregulation of cardiomyopathy-associated pathways—including hypertrophic and dilated cardiomyopathy. Key EV proteins such as Atp2a2, Lmna, Tgfb3, Agt, and Sgce, crucial for myocardial function, calcium homeostasis, and vascular signaling, were suppressed, suggesting impaired fetal cardiac programming. Additional pathway analyses indicated disruption of metabolic and glycosylation processes and upregulation of vesicle transport and neurodevelopment-related proteins. These findings position placental EVs as sensitive indicators of in utero drug exposure and propose a mechanistic link between maternal opioid use and altered fetal cardiovascular development. This work establishes a novel systems-level foundation for developing EV-based diagnostics and interventions targeting opioid-induced developmental risk.