The evaluation of the health risk of microplastics (MPs) on mammals has been limited compared to a number of studies on the toxicological effects of MPs on aquatic organisms. To bridge this knowledge gap, we use a mouse model to study the biological effects of long-term exposure to MPs at an environmentally relevant concentration based on the deuterium oxide (D2O) global omics relative quantification (DOLGOReQ) method recently developed by our group. In the experimental group, ICR mice were given normal drinking water containing MPs at a concentration of approximately 400 ng of polystyrene (50 nm) or polyethylene (1-4 μm) daily. Mice in the control group were fed drinking water rich in 5% D2O. After 5 or 24 weeks of the exposure to MPs, serum lipids were extracted at the expense of mice. Relative quantification of serum lipids by DOLGOReQ showed that 5 triacylglycerols were down-regulated in the polystyrene group, and one sphingomyelin was down-regulated in the polyethylene group 5 weeks after exposure to MP. After 24 weeks of exposure to MP, one lysophosphatidylcholine was down-regulated in the polystyrene and polyethylene groups. In addition, 11 triacylglycerols were down-regulated and 3 sphingomyelins were up-regulated in the polyethylene group. Finally, we sought to interpret the changes in lipid species resulting from exposure to MP in the context of lipid metabolism.