In this work, we combine microfluidics and quantitative fluorescence microscopy to characterize the uptake and release dynamics of polystyrene (PS) microplastics across various tissue cell types. We show that macrophages exhibit a high capacity to engulf microplastics, and epithelial, endothelial, fibroblast, and T cells all display certain degrees of microplastics uptake. Using a series of in vitro assays, we systematically examine how physiologically relevant fluidic parameters—such as viscosity, hydrostatic pressure, and osmotic stress—modulate PS microplastic transport in these cells. We find that extracellular fluid viscosity has a significant and consistent effect on microplastic dynamics across all tested cell types. Increasing viscosity to levels typical of bodily fluids (1.5–2 cP) enhances PS uptake by up to fivefold and suppresses its release. However, this elevated viscosity also reduces transepithelial transport, as microplastics become trapped within tissue cells. Furthermore, we investigate the functional consequences of microplastic exposure on cell behavior. While proliferation is largely unaffected, we observe that microplastics impede cell migration in specific cell types, notably fibroblasts, both at the single-cell level and in collective wound-healing assays. Together, our findings reveal a key role for fluidic environment in regulating microplastic–cell interactions and highlight potential impairments in fundamental tissue cell functions caused by microplastic accumulation.