Aging refers to the intracellular accumulation of reactive oxygen species that damages proteins, DNA, and lipids. As alterations in lipid metabolism may trigger metabolic disorders and the onset of metabolic diseases, changes in lipid profiles can be closely related to aging. In this study, a comprehensive lipidomic comparison between 4- and 25-month-old mice was performed to investigate age-induced changes in the lipid profiles of mouse serum, kidney, and heart using nanoflow ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Quantitative analysis of 279 of the 542 identified lipids revealed significant changes upon aging, mainly showing decreased levels in the three types of samples. Exceptionally, most triacylglycerols showed significant increases in heart tissue. The kidney was influenced more by aging than the serum and heart. The highly abundant lipids in each lipid class with significant decreases (> 2-fold, p < 0.01) were lysophosphatidic acid 18:1, lysophosphatidylinositol 20:4, and ceramide d:18:1/24:0 in serum; lysophosphatidylglycerol 16:0 in heart tissue; and eight phosphatidylethanolamines (20:4, 22:6, 36:2, 36:3, 38:4, 38:5, 38:6, 40:6, and 40:7), two cardiolipins (72:7 and 72:8), and lysophosphatidylcholine 18:0 in kidney tissue. The findings indicate the potential of lipidomic analysis to study characteristic age-related lipid changes.