Abstract: To elucidate the size-dependent neurotoxic effects of atmospheric particulate matter while minimizing confounding contributions from particle-bound chemical constituents, polystyrene (PS) micro- and nanoplastics with nominal diameters of 0.1, 1.0, 2.5, and 10.0 μm were employed as a well-controlled in vitro model. Human neuroblastoma cell lines were exposed to these particles, and the differential cytotoxic, oxidative, and functional responses elicited by each size fraction were systematically evaluated. The results revealed that the half-maximal inhibitory concentrations of PS micro-nanoplastics differed across particle sizes, exhibiting a size-dependent trend. At lower exposure concentrations, oxidative stress indicators—including malondialdehyde and reactive oxygen species—increased with decreasing particle size, whereas glutathione levels decreased accordingly. In contrast, the levels of inflammatory cytokines markers, including human interleukin-6, interleukin-1β, and tumor necrosis factor-α, showed a size-dependent increase. Overall, PS micro- and nanoplastics exerted size-dependent influences on neural cell viability, oxidative stress, and neuroinflammatory responses, with smaller particles demonstrating more pronounced neurotoxic effects. Using the PS micro- and nanoplastics model, this study demonstrates that, to some extent, atmospheric particulate matter of different sizes exhibits differential neurotoxicity when the chemical component dimension is excluded. The smaller the particle size, the stronger the neurotoxic effects on neural cells. These findings provide scientific data for the precise assessment of health risks posed by atmospheric particulate matter of varying sizes in real-world environments.