The emerging paradigm on plastic pollution in marine environments is that microsize particles (MPs) have far more subtle effects than bigger fragments, given their size range overlapping with that of particles ingested by filter-feeders. The impacts include gut blockage, altered feeding and energy allocation, with knock-on effects on widespread physiological processes. This study investigated whether ingestion of polystyrene MPs (PS-MPs) triggers protective processes in marine mussels. The Multixenobiotic resistance (MXR) system is a cytoprotective mechanism acting as an active barrier against harmful xenobiotics and a route of metabolite detoxification. Both larvae and adults were employed in laboratory experiments with different concentrations of 3-μm PS-MPs (larvae), and 3-μm and 45-μm PS-MPs (adults) matching size range of planktonic food through the mussel lifecycle. Embryos grown in the presence of 3-μm PS-MPs showed significant reduction of MXR activity and down-regulation of ABCB and ABCC transcripts encoding the two main MXR-related transporters P-glycoprotein and the Multidrug resistance-related protein, respectively. In adults, effects of PS-MPs were assessed in haemocytes and gills, which showed different modulation of MXR activity and ABCB/ABCC expression according to MP size (haemocyte and gills) or particle concentration (haemocyte). These data showed that modulation of MXR activity is part of a generalized response triggered by particle ingestion.