At present, nanoplastics have been detected in food and the environment, but they have serious impacts on the human body. As one of the typical representatives of nanoplastics, polystyrene (PS) is generally used as an experimental object. Few studies found that PS could modulate the formation of amyloid fibrils, leading to the occurrence of diseases. However, its submicron-scale effects remain elusive. Thus, this study aimed to explore the interaction between PS of particle size 100-500 nm and hen egg-white lysozyme (HEWL). The results showed that PS of size 400 nm markedly promoted the primary nucleation step of amyloid fibril formation, and fibrils had more small fragments compared with PS of size 100 nm in the control and sample groups. PS of larger particle size changed the spatial structure of HEWL significantly. This study analyzed the experimental results from the perspective of protein corona and thermodynamics. The study confirmed that PS was able to form protein corona with HEWL in the initial stage, which was mainly driven by hydrophobic interactions. More importantly, the interface and junction of the protein corona were the main sites for the formation of amyloid fibrils. This study highlighted the role of submicron particle size and discussed the toxic effects of nanoparticles.