Many observational studies in North American lakes have documented decreases in phytoplankton abundance after the invasion of the zebra mussel (Dreissena polymorpha). However, few field experiments have examined in detail the effect of zebra mussels on phytoplankton abundance and species composition over an extended period. Replicated in situ mesocosms were used to evaluate the impact of natural densities of zebra mussels on phytoplankton and ciliate biovolume, and algal species composition over a 5-week period in a habitat that lacked extant mussel populations. Mussel biomass used in the experiment was determined using a regression model based on a data analysis that predicts zebra mussel biomass from total phosphorus concentration. Within 1 week, zebra mussels decreased phytoplankton biovolume by 53% and ciliate biovolume by 71%. The effect of zebra mussels on ciliate biovolume was sustained throughout the study. However, the effect of zebra mussels on phytoplankton abundance gradually waned over the remaining 4 weeks of the experiment, such that the declining effect of zebra mussels could not be explained by a shift towards less edible and/or faster growing algal species. The mussels’ declining condition could help to explain the effect observed over the course of the experiment.