The contamination of marine ecosystems with microplastics, such as the polymer polyethylene, a commonly used component of single-use packaging, is of global concern. Although it has been suggested that biodegradable polymers, such as polylactic acid, may be used to replace some polyethylene packaging, little is known about their effects on marine organisms. Blue mussels, Mytilus edulis, have become a “model organism” for investigating the effects of microplastics in marine ecosystems. We show here that repeated exposure, over a period of 52 days in an outdoor mesocosm setting, of M. edulis to polyethylene microplastics reduced the number of byssal threads produced and the attachment strength (tenacity) by ∼50%. Exposure to either type of microplastic altered the haemolymph proteome and, although a conserved response to microplastic exposure was observed, overall polyethylene resulted in more changes to protein abundances than polylactic acid. Many of the proteins affected are involved in vital biological processes, such as immune regulation, detoxification, metabolism and structural development. Our study highlights the utility of mass spectrometry-based proteomics to assess the health of key marine organisms and identifies the potential mechanisms by which microplastics, both conventional and biodegradable, could affect their ability to form and maintain reefs.