Microplastics (MPs) have become a worldwide issue because of their persistence in marine organisms, their accumulation in the food chains, and their inevitable human exposure. Silymarin is a therapeutic agent used in the treatment of multiple liver diseases. The study aimed to explore the potential therapeutic effect of 2 weeks of silymarin treatment against the effects of two sizes of 1 and 5 μm of polystyrene microplastic particles (PS-MPs) on the liver after 6 weeks of the study period. Animals were divided into negative and positive control, silymarin group (200 mg/kg), PS-MP groups of 1 and 5 μm size (0.02 mg/kg), 1 μm size PS-MPs + silymarin group, and 5 μm size PS-MPs + silymarin group, animals were treated once daily by oral gavage. The study revealed that hepatotoxicity induced by two diameters of PS-MPs with marked destructive effects of 1 μm size greater than that of 5 μm size and the effective therapeutic role of silymarin in improving PS-MPs caused hepatotoxic injury, particularly with 5 μm PS-MPs size; through regression of liver pathology (hepatic cell lysis, inflammation, fibrotic changes, and collagen deposition), restoring ultrastructure morphology (mitochondrial destruction and accumulation of lipid droplets accumulation). It improved liver function by reducing serum AST, ALT, LDH, total cholesterol, and triglycerides. It also reduced oxidative stress by reducing serum MDA, increasing TAC, down-regulation of iNOS, and up-regulation of Nrf2 and HO-1 hepatic gene expression. Furthermore, it relieved pyroptosis by negatively regulating the expression of the NLRP3, caspase-1, and IL-1β hepatic gene expression. The results suggested silymarin’s therapeutic effects in treating PS-MPs-induced hepatotoxic injury and recommended its use as a postexposure treatment for a longer duration.