Investigating the long-term effects of microplastics (MPs) in vivo is necessary for evaluating its biological toxicity. Previously, we showed that MPs elicit vascular dysfunctions in atherosclerotic mice. However, the effects of longterm treatment with environmental levels of MPs on biological functions and RNA expression profiles in wild type mice are unknown. Here, C57BL/6 mice were administered 1000 mu g/L MPs through their drinking water for 180 days. Transcriptomic analyses, biochemical analysis, and histopathological examination were conducted to determine the key signals and molecular mechanisms triggered by MPs in vivo using whole transcriptome sequencing, enzyme-linked immunosorbent assay, and histopathological analysis. Notably, our data revealed that MPs aggravated vascular lesions and organ injuries, particularly liver, kidney, and heart injuries. Additionally, MPs exacerbated oxidative injuries by inhibiting the activities of antioxidant enzymes and increasing the levels of the serum biochemistry indicator of organ damage. RNA sequencing of vascular tissues showed that 674 mRNAs, 39 lncRNAs, 196 miRNAs, and 565 circRNAs were abnormally expressed in MPs-treated mice compared with the untreated group. Pathway enrichment analyses identified pathways linked to the toxicity of MPs, including lysosomal, NOD-like receptor, and peroxisome proliferator-activated receptor pathways. Additionally, competing endogenous RNA networks were constructed and hub RNAs were identified using bioinformatics analysis. Taken together, our data suggested that toxicity induced by long-term exposure to MPs continually presents with extensive changes in biological features and global gene expression profiles. Our data provides new insights into the biological toxicity of MPs.