Considerable evidence suggests that metabolic abnormalities are associated with neurodegenerative diseases. This study aimed to conduct a systematic metabolic analysis of Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). Human and mouse model microarray datasets were downloaded from the Gene Expression Omnibus database. The metabolic genes and pathways were collected from the Recon 3D human metabolic model. Drug and target information was obtained from the DrugBank database. This study identified ATP1A1, ATP6V1G2, GOT1, HPRT1, MAP2K1, PCMT1 and PLK2 as key metabolic genes that were downregulated in AD, PD and HD. We screened 57 drugs that target these genes, such as digoxin, ouabain and diazoxide. This study constructed multigene diagnostic models for AD, PD and HD by using metabolic gene expression profiles in blood, all models showed high accuracy (AUC > 0.8) both in the experimental and validation sets. Furthermore, analysis of animal models showed that there was almost no consistency among the metabolic changes between mouse models and human diseases. This study systematically revealed the metabolic damage among AD, PD, and HD and uncovered the differences between animal models and human diseases. This information may be helpful for understanding the metabolic mechanisms and drug development for neurodegenerative diseases.