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Polystyrene micro- and nanoplastics (PS-MNPs) are emerging environmental pollutants with potential implications for human health. This study investigated the cytotoxic effects of PS particles by using two different sizes of PS-MNPs (0.25 µm and 1 µm) on non-small cell lung cancer (A549, H460), small cell lung cancer (DMS53, H372), and normal lung epithelial (BEAS-2B) cells as well as on human-derived lung organoids. Neither PS-MPs nor PS-NPs interfered with cell viability or proliferation at lower concentrations (< 30 µg/cm2, equivalent to 50 µg/ml). Intracellular kinetic assays revealed that non-malignant (BEAS-2B) lung cells had the strongest turnover of PS-NPs compared to malignant cells. Since PS-NPs exhibited more pronounced cellular effects, additional analyses focused on their impact. Furthermore, we observed significantly increased migration, prolonged S-phase arrest with induced DNA damage, and oxidative stress in non-malignant (BEAS-2B) lung cells. Thus, our data suggest that BEAS-2B cells exhibit the highest sensitivity to PS-NPs. These cells displayed decreased base excision repair capacity and increased activation of survival pathways including AKT and ERK phosphorylation after PS-NP treatment. PS-NP internalization and increase of signal pathways were validated in a physiological lung organoid setting. Our findings suggest that while PS-NPs do not significantly affect the malignant behavior of cancer cells, they could promote malignant features in normal lung cells through the induction of survival pathways, migration, and altered stress response mechanisms.