The degradation of marine plastic debris poses a threat to marine organisms by fragmenting into micro and nanoscale pieces and releasing a complex chemical leachate into the water. Numerous studies have investigated the separate aspects of the complex danger from plastic such as microplastic ingestion and exposure to individual chemicals. However, few studies have examined the holistic threat of plastic exposure and the synergistic impacts of chemical mixtures. The objective of this study was to measure changes in gene expression of gill and gonadal tissue of the eastern oyster, Crassostrea virginica, in response to plastic debris exposure during their first year, using RNASeq to explore multiple types of physiological responses. Shell and polyethylene terephthalate plastic were used as substrate for the settlement of larval oysters in a settlement tank. Substrate pieces were then transferred to metal cages and outplanted in pairs, shell cage and plastic cage, onto restoration reefs in the St. Marys River, Maryland, USA. After 10 months of growth, the oysters were collected, gill and gonadal tissue removed, and sex identified. The tissues of six oysters from each sex and substrate type were then used in RNASeq. Both gill and gonadal tissue had altered expression of immune and stress-response genes in response to plastic exposure. Genes upregulated in response to plastic were enriched for gene ontology functions of proteolysis and fibrinolysis. Downregulated genes were involved in shell biomineralization and growth. One male oyster exposed to plastic had feminized gene expression patterns despite developing mature sperm, suggesting plastic leachate can alter gene expression and shift protandric individuals to develop as females.