Hypoxia has been observed in the central basin of Lake Erie for decades. To understand the impact of various controlling factors, we analyze a record of hypoxic extents for Lake Erie for 1985-2012 and develop a parsimonious model of their interannual variability. We find that the 2012 North American drought and accompanying low tributary discharge was associated with a record-breaking hypoxic event in Lake Erie, whereas a record-setting harmful algal bloom in 2011 was likely associated with only mild hypoxia. River discharge and the timing of nutrient input therefore impact western basin bloom growth and central basin oxygen demand in distinct ways that merit further investigation. Overall, April to June tributary discharge, May to July soluble reactive phosphorus loading, July wind stress, and June northwesterly wind duration explain 82% of the interannual variability of hypoxia, and discharge alone explains 39%, indicating that meteorological factors need to be considered in the development of nutrient management strategies, especially as both extreme precipitation events and droughts become more frequent under a changing climate.