General circulation models have suggested that the number of extreme floods and droughts will increase with climate change; recent analyses of satellite data have demonstrated that these increases have been higher than predicted. Coastal systems, like the Delaware Estuary, can be vulnerable to such extreme weather events. In analyzing the 100- and 80-year records of the two major rivers of the Delaware Estuary, we find that about 20% of the very large and 50% of the extreme daily discharges occurred in the current decade (2001–2011), and this represents a significant increase in flood occurrence compared with the rest of the discharge record. This is consistent with predictions of increased extreme weather conditions (inundation and drought) from climate change. Previously, we had characterized the Delaware Estuary as usually well mixed in the summer without significant bottom water oxygen depletion, based on our 30-year research efforts, and a 44-year agency monitoring record. In the summer of 2006, an extreme river discharge pushed the Delaware Estuary salinity gradient further downstream than seen in our research record and induced a nutrient influx to the nutrient-poor lower bay regions. As a result, stratification apparently allowed for a rapid phytoplankton biomass increase similar to the spring bloom phenomenon. A simple modeling exercise supports the idea that although unusual for this estuary in the summer, oxygen depletion occurred in response to the bloom biomass falling and decomposing in the isolated bottom waters. Using the summer 2006 anomalous discharge event and the resultant stratification as an illustration, and considering the significant increase in large and extreme floods in the last decade, we suggest that the typology of the Delaware Estuary is shifting as a result of climate change.