Microplastics (MPs), plastics with particles smaller than 5 mm, have been found almost in every corner of the world, especially in the ocean. Due to the small size, MPs can be ingested by animals and enter the marine trophic chain. MPs can affect animal health by physically causing damage to the digestive tract, leaking plastic chemical components, and carrying environmental pollutants and pathogens into animals. In this study, impacts of MPs ingestion on gut microbiota were investigated. Filter feeding mussels were exposed to “virgin” and “weathered” MPs at relatively realistic concentration 0.2 mg L−1 (“low”) and exaggerated concentration 20 mg L−1 (“high”) for 6 weeks. Influence in mussel gut microbiota was investigated with 16S rRNA gene high-throughput sequencing. As compared with non-exposed mussels, alteration of gut microbiota was observed after mussels were exposed to MPs for 1 week, 3 weeks, 6 weeks, and even after 8-day post-exposure depuration. Potential human pathogens were found among operational taxonomic units (OTUs) with increased abundance induced by MP-exposure. Faecal pellets containing microorganisms from altered gut microbiota and MPs might further influence microbiota of surrounding environment. Our results have demonstrated impacts of MP-exposure on mussel gut microbiota and suggested possible consequent effects on food quality, food safety, and the well-being of marine food web in the ecosystem for future studies.