Based on the average level of seafood consumption in the United States (U.S.), the 2010 Dietary Guidelines for Americans encourages citizens to double their intake to improve the health of their diets. The future availability of seafood, however, is threatened by overfishing, unsustainable seafood farming practices, ocean pollution and acidification, and other factors. The growing global population and advancing ecological threats such as climate change are placing increasing demands and constraints on U.S. and global seafood supplies. Waste reduction has the potential to support increased seafood consumption without further stressing aquatic resources. It is essential to quantify waste levels in order to effectively target and design waste reduction interventions. Accordingly, we used previous multi-country regional research and updated datasets to calculate a country-specific (U.S.) estimate of seafood loss for the years 2009–2013. We estimate that 40–47% of the edible U.S. seafood supply went uneaten in this period. The greatest portions of this loss occurred at the levels of consumers (in and out of home) (51–63% of loss attributed to consumption), bycatch discarded by commercial fishers (16–32%), and in distribution and retail operations (13–16%). Based on conservative estimates, this waste represents 208 billion grams of protein, 1.8 trillion mg of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (i.e., omega-3 fatty acids), and 1.1 trillion kilocalories. The seafood that is lost could fill 36% of the gap between current consumption and U.S. Department of Agriculture-recommended levels. As another way of understanding the magnitude of loss, this lost seafood could provide the total yearly target quantity of protein for 10.1 million men or 12.4 million women, EPA + DHA for 20.1 million adults, and calories for 1.5 million adults. The lost nutrition estimates we provide are meant to be illustrative of the issue’s significance and magnitude. While a significant portion of the loss could be prevented or recovered for human consumption, we do not intend to suggest that all of it could or should become food for humans. Bycatch is generally best left in the water; some seafood loss is not culturally acceptable, marketable, nutritious or safe; and a portion of loss is also unavoidable. Instead, we discuss waste prevention strategies involving governments, businesses, and consumers that can be employed to reduce seafood loss and create a more efficient and sustainable seafood system..