We examined seasonal dynamics of zooplankton at an offshore station in Lake Michigan from 1994 to 2003 and 2007 to 2008. This period saw variable weather, declines in planktivorous fish abundance, the introduction and expansion of dreissenid mussels, and a slow decline in total phosphorus concentrations. After the major expansion of mussels into deep water (2007–2008), chlorophyll in spring declined sharply, Secchi depth increased markedly in all seasons, and planktivorous fish biomass declined to record-low levels. Overlaying these dramatic ecosystem-level changes, the zooplankton community exhibited complex seasonal dynamics between 1994–2003 and 2007–2008. Phenology of the zooplankton maximum was affected by onset of thermal stratification, but there was no other discernable effect due to temperature. Interannual variability in zooplankton biomass during 1994 and 2003 was strongly driven by planktivorous fish abundance, particularly age-0 and age-1 alewives. In 2007–2008, there were large decreases in Diacyclops thomasi and Daphnia mendotae possibly caused by food limitation as well as increased predation and indirect negative effects from increases in Bythotrephes longimanus abundance and in foraging efficiency associated with increased light penetration. The Bythotrephes increase was likely driven in part by decreased predation from yearling and older alewife. While there was a major decrease in epilimnetic–metalimnetic herbivorous cladocerans in 2007–2008, there was an increase in large omnivorous and predacious calanoid copepods, especially those in the hypolimnion. Thus, changes to the zooplankton community are the result of cascading, synergistic interactions, including a shift from vertebrate to invertebrate planktivory and mussel ecosystem impacts on light climate and chlorophyll.