Plastic has been largely detected in estuarine environments and represents major concern towards aquatic living organisms. The present study evaluates the impact of microplastics (MPs) and nanoplastics (NPs) under realistic exposure conditions. Scrobicularia plana individuals were exposed to low concentrations (0.008, 10, and 100 µg L−1) of environmental MPs and NPs as well as to standard PS NPs, as a comparison condition. The aim of this study was to understand the ecotoxicological effects of environmental plastic particles on S. plana gills and digestive glands but also to compare the effects of plastic polymers size in order to highlight if the size could induce different toxicity profiles within this model organism, at different levels of biological organization. Results showed a differential induction of detoxification enzymes (CAT, GST), immunity (AcP), DNA damage processes as well as a differential effect on behavior and condition index of animals depending upon the type of plastic, the size, the concentration tested, and the type of organ. This study underlines the necessity of testing (i) plastics collected from the environment as compared to standard ones and (ii) the effect of size using plastics coming from the same batch of macrosized plastics. This study concludes on the future need directions that plastic-based studies must take in order to be able to generate a large quantity of relevant data that could be used for future regulatory needs on the use of plastic.