The effect of active acupoints versus inactive acupoints in treating hypertension is not well documented. Metabolic phenotypes, depicted by metabolomics analysis, reflect the influence of external exposures, nutrition, and lifestyle on the integrated system of the human body. Therefore, we utilized high-performance liquid chromatography tandem mass spectrometry to compare the targeted metabolic phenotype changes induced by two different acupoint treatments. The clinical outcomes show that active acupoint treatment significantly lowers 24-hour systolic blood pressure but not diastolic blood pressure, as compared with inactive acupoint treatment. Furthermore, distinctive changes are observed between the metabolomics data of the two groups. Multivariate analysis shows that only in the active acupoint treatment group can the follow-up plasma be clearly separated from the baseline plasma. Moreover, the follow-up plasma of these two groups can be clearly separated, indicating two different post-treatment metabolic phenotypes. Three metabolites, sucrose, cellobiose, and hypoxanthine, are shown to be the most important features of active acupoint treatment. This study demonstrates that metabolomic analysis is a potential tool that can be used to efficiently differentiate the effect of active acupoints from inactive acupoints in treating hypertension. Possible mechanisms are the alternation of hypothalamic microinflammation and the restoration of host-gut microbiota interactions induced by acupuncture.