Living organisms are now constantly exposed to microplastics and nanoplastics (MNPLs), and besides their toxic potential, they can also act as carriers of various hazardous elements such as heavy metals. Therefore, this study explored possible interactions between polystyrene microplastics (PSMPLs) and two metal pollutants: cadmium chloride (CdCl2) and silver nitrate (AgNO3). To better understand the extent of biological effects caused by different sizes of PSMPLs, we conducted in vivo experiments with five doses (from 0.01 to 10 mM) that contained polystyrene particles measuring 4, 10, and 20 µm in size on Drosophila larvae. Additional experiments were performed by exposing larvae to two individual metals, CdCl2 (0.5 mM) and AgNO3 (0.5 mM), as well as combined exposure to PSMPLs (0.01 and 10 mM) and these metals, in an attempt to gain new insight into health risks of such co-exposure. Using transmission electron microscopy imaging, we managed to visualize the biodistribution of ingested PSMPLs throughout the fly’s body, observing the interactions of such plastics with Drosophila intestinal lumen, cellular uptake by gut enterocytes, the passage of plastic particles through the intestinal barrier to leak into the hemolymph, and cellular uptake by hemocytes. Observations detected size and shape changes in the ingested PSMPLs. Egg-to-adult viability screening revealed no significant toxicity upon exposure to individual doses of tested materials; however, the combined exposure to plastic and metal particles induced aggravated genotoxic effects, including intestinal damage, genetic damage, and intracellular oxidative stress (ROS generation), with smaller sized plastic particles + metals (cadmium and silver) causing greater damage.