The production of plastics worldwide has been instrumental in the progress of modern society, while the increasing accumulation of plastics castoff in oceans, soils and anywhere else has become a major pressure source on environmental sustainability and animal health. Meanwhile, from a biological perspective, our understanding of the toxicological fingerprints of plastics, especially microplastics (MPs), is still poor. Here, we reported a phenomenon of hepatotoxicity dominated by MPs in the form of polystyrene (PS), was observed in mice model systems and cellular assays. Apoptosis and necroptosis related to the size of particles were seen upon PS-MPs introduction, as revealed by transmission electron microscopy, fluorescence microscopy, flow cytometry, and quantitative analysis of signaling pathways in vivo and vitro. Collectively, the current study demonstrated that the levels of liver cell injury caused by PS-MPs were negatively correlated with the particle diameters. Small-sized particles (1–10 μm) induced cell death primarily as necroptosis whereas the large-sized particles (50–100 μm) mainly induced apoptosis, which was directly accomplished by PTEN/PI3K/AKT signaling axis and its targeted autophagy flux. More interestingly, inhibition of autophagy not only alleviated PS-MPs-triggered cell death, but also changed the form of death injury to a certain extent. This uncovered crosstalk relationship opens up a new avenue for investigating the biological and toxicological effects of MPs, and may provide important insights for preventing and limiting of health hazards from MPs.