Benthic communities in Long Island Sound (LIS) have experienced over 150 years of commercial shellfishing and excess nutrient loading (eutrophication) which causes hypoxia. We established an ecological baseline using a combination of live, dead, archaeological, and fossil material to investigate the impacts of these stressors on the molluscan community. We expected that ecological change would increase with eutrophication-hypoxia west towards New York City. Instead we found that taxonomic similarity, rank-order abundance, and drilling frequency are more strongly controlled by commercial fishing pressure than by decreasing dissolved oxygen. Commercial fisherman collecting quahog clams (Mercenaria mercenaria), physically disrupt surface-dwelling organisms and also kill large numbers of predatory gastropods, including the channeled whelk, Busycotypus canaliculatus, and the drilling moonsnails Neverita duplicata and Euspira heros, to protect hard clam stocks. As a result, areas dredged by commercial fishermen yield fewer shells with drill-holes and fewer surface-dwelling organisms than unfished sites. In spite of recent reductions in lobster fishing, crushing predation by crabs and lobsters on clams has been suppressed below baseline levels throughout LIS, even in the well oxygenated east. The absence of a clear relationship between eutrophication-hypoxia and ecological change questions the effectiveness of nitrogen reduction alone as a restoration strategy. LIS fossils revealed a relatively ancient loss of those mollusks associated with seagrass and oyster habitats (e.g., oysters, Crassostrea virginica; jingle shells, Anomia simplex; scallops, Argopecten irradiens; and the gastropod Bittiolum alternatum) that predates the accumulation of dead shells and underscores the need for older material to reveal the shifting baseline. The interactive nature of multiple stressors means that past overfishing may have dampened the response of communities in LIS to eutrophication or inhibited their capactiy to recover. The unexpected role of hypoxic areas protected from commercial fishing as refuges highlights the utility of no-take marine preserves in eutrophied estuaries worldwide.