The entry of micro- and nanoplastics (MNPs) into the human body is inevitable. They enter blood circulation through ingestion, inhalation, and dermal contact by crossing the gut-lung-skin barrier (the epithelium of the digestive tract, the respiratory tract, and the cutaneous layer). There are many reports on their toxicities to organs and tissues. This paper presents the first thorough assessment of MNP-driven bloodstream toxicity and the mechanism of toxicity from the viewpoint of both MNP and environmental co-pollutant complexes. Toxic impacts include plasma protein denaturation, hemolysis, reduced immunity, thrombosis, blood coagulation, and vascular endothelial damage, among others, which can lead to life-threatening diseases. Protein corona formation, oxidative stress, cytokine alterations, inflammation, and cyto- and genotoxicity are the key mechanisms involved in toxicity. MNPs change the secondary structure of plasma proteins, thereby preventing their transport functions (for nutrients, drugs, oxygen, etc.). MNPs inhibit erythropoiesis by influencing hematopoietic stem cell proliferation and differentiation. They cause red blood cell and platelet aggregation, as well as increased adherence to endothelial cells, which can lead to thrombosis and cardiovascular disease. White blood cells and immune cells phagocytose MNPs, provoking inflammation. However, research gaps still exist, including gaps regarding the combined toxicity of MNPs and co-pollutants, toxicological studies in human models, advanced methodologies for toxicity analysis, bioaccumulation studies, inflammation and immunological responses, dose-response relationships of MNPs, and the effect of different physiochemical characteristics of MNPs. Furthermore, most studies have analyzed toxicity using prepared MNPs; hence, studies must be undertaken using true-to-life MNPs to determine the real-world scenario. Additionally, nanoplastics may further degrade into monomers, whose toxic effects have not yet been explored. The research gaps highlighted in this review will inspire future studies on the toxicity of MNPs in the vascular/circulatory systems utilizing in vivo models to enable more reliable health risk assessment.