Hypolimnetic hypoxia is expanding globally due to anthropogenic eutrophication and climate warming. Muskegon Lake, a Great Lakes estuary, experiences annually recurring hypoxia, impairing ecological, social, and economic benefits. Using high-frequency, time-series Muskegon Lake Observatory (MLO) data, we quantified the dynamics of hypoxia and developed a hypoxia severity index to estimate the spatiotemporal extent of hypoxia during 2011–2021. We also analyzed United States Geological Survey’s temperature and discharge data on the Muskegon River to explain the annual variability in the hypoxia severity index. Severe hypoxia occurred in warmer years with greater stratification, fewer wind mixing events, warmer winter river temperatures, and less winter and spring precipitation, as in 2012 and 2021. Conversely, milder hypoxia was prevalent in colder years with a later stratification onset, more mixing events, colder river temperatures, and more winter and spring precipitation, as in 2015 and 2019. Thus, knowledge of environmental conditions prior to the onset of stratification may be useful for predicting the potential severity of hypoxia for any year. While consistent multi-year trends in hypoxia were not discernible, our findings suggest that temperature and precipitation are major drivers of hypoxia and that as surface waters warm, it will lead to the further deoxygenation of Earth’s inland waters.