The transgenic mouse APP/PS1 is widely employed by neuroscientists because reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. In this study, serum samples from APP/PS1 mice (n = 30) and wild-type controls (n = 30) were analyzed using a metabolomic multiplatform based on the combination of gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry, in order to obtain wide information about serum metabolome. Metabolic profiles showed significant differences between the groups of study, and numerous metabolites were identified as potential players in the development of Alzheimer-type disorders in this transgenic model. Pathway analysis revealed the involvement of multiple metabolic networks in the underlying pathology, such as deficiencies in energy metabolism, altered amino acid homeostasis, abnormal membrane lipid metabolism, and other impairments related to the integrity of the central nervous system. It is noteworthy that some of these metabolomic markers are in accordance with pathological alterations observed in human Alzheimer's disease, while others have not been previously described. Therefore, these results demonstrate the potential of metabolomics and the use of transgenic animal models to understand the pathogenesis of Alzheimer's disease.