Abstract: Ultra-high performance liquid chromatography-quadrupole-electrostatic field orbital trap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS) was used to analyze the saponin components in sun-dried American ginseng and red American ginseng. The principal component analysis, orthogonal partial least squares discriminant analysis, and differential component analysis were employed to compare the differential saponins in these two processed products of ginseng. A Supelco C18 column (3.0 mm×50 mm, 2.7 μm) was used with 0.1% formic acid in water and acetonitrile as the mobile phase for gradient elution. Full primary MS scan and secondary MS scan were performed by an electrospray ionization source under both positive and negative ion modes. A total of 66 saponin components are identified in sun-dried American ginseng and red American ginseng, among which 31 are differential saponins, including 14 PPD-type, 11 PPT-type, and 6 other types. Among the 14 PPD-type differential saponins identified by screening, 3 ginsenosides are higher in sun-dried American ginseng, including ginsenoside Rc, malonyl ginsenoside Rb₂, and acetyl ginsenoside Rg₁, while 11 ginsenosides are higher in red American ginseng, including prototypical saponins, such as ginsenoside Rd, ginsenoside Rb₂, and some rare saponins (ginsenoside Rg₃, ginsenoside Rs₃, ginsenoside Rh₂, and others). Among the 11 PPT-type differential saponins, 3 ginsenosides are found with high content in sun-dried American ginseng, including malonyl ginsenoside Rg₁, malonyl ginsenoside Re and acetyl ginsenoside Re, while 8 ginsenosides are found with high content in red American ginseng, including prototypic saponins, such as ginsenoside Rg₂, American ginsenoside R₂ and some rare saponins (ginsenoside Rh₁, ginsenoside Rg₄). Additionally, 6 other types of ginsenosides, all of which are rare saponins and more abundant in red ginseng. Acetyl- and malonyl-substituted ginsenosides are more abundant in sun-dried American ginseng, while most of the rare saponins are more abundant in red American ginseng. Based on the results of the tandem MS scans of the identified compounds, the mass spectrometric fragmentation pathways of the four types of saponins were summarized, and the possible transformation processes of some saponins were enumerated. Due to the effect of temperature, the sugar group at the C-20 position is prone to hydrolysis and deglycosylation, followed by isomerization or dehydration. Some of the prototypical saponins are converted into rare saponins, in addition to high temperature promoted chemical reactions, such as deacetylation and depropanediylation. This method is accurate and efficient, and can provide a theoretical basis for the pharmacological material basis and quality evaluation of American ginseng.