BACKGROUND: Active dietary flavonoids are a promising resource for novel drug discovery. Sweet potato, a widely cultivated functional crop, is abundant in flavonoids. However, the active ingredients associated with acute myeloid leukemia (AML) treatment and their underlying mechanisms have not been reported to date. OBJECTIVE: This study aims to identify novel drugs against AML from sweet potato by integrating metabolomics analysis, network pharmacology, and experimental validation. METHODS: Firstly, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed to analyze the major constituents in sweet potato. Then, nine active ingredients were selected for validation of their anti-leukemia effects. Subsequently, three of them underwent network pharmacology analyses and RESULTS: Firstly, the flavonoid content of stem, leaves, flesh, and peel from 13 sweet potato cultivars was examined. The leaves of Nanshu 017 exhibited the highest flavonoid content of 2.27% dry weight (DW). Then, an extract derived from these leaves was employed for CONCLUSION: In summary, sweet potato leaves extract possesses an antileukemic effect while cynaroside, nepitrin, and yuanhuanin demonstrate potential as treatments for AML.