Metaplasia is a well documented and deleterious effect of crude oil components on bivalved molluscs, including oysters. This reversible transformation of one cell type to another, is a common response to petroleum-product exposure in molluscs. It has been shown experimentally in previous work that eastern oysters (Crassostrea virginica) exposed to petroleum products will exhibit metaplasia of digestive tissues. Here we document for the first time that wild adult oysters inhabiting coastal waters in the northern Gulf of Mexico during and in the aftermath of the Deepwater Horizon oil spill (2010) exhibited metaplasia in both ctenidia and digestive epithelia at significantly higher levels than geographic controls of C. virginica from Chesapeake Bay. Both ctenidial (respiratory and suspension feeding) and digestive tract tissues exhibited significantly higher frequencies of metaplasia in specimens from the Gulf of Mexico compared to those from Chesapeake Bay. Metaplasia included the loss of epithelial cilia, transformations of columnar epithelia, hyperplasia and reduction of ctenidial branches, and vacuolization of digestive tissues. Evidence for a reduction of metaplasia following the oil spill (2010-2013) is suggestive but equivocal.